New animal model for elimination of latent TB

An animal model could help researchers develop shorter courses of treatment for latent Read more

Transplant research: immune control via Fc receptors on T cells

Emory transplant researchers have identified a control mechanism the immune system uses to tamp down chronic inflammation. The findings provide insight into how some people were able to stop taking immunosuppressive drugs after kidney transplant. In addition, they may be important for a full understanding of how many drugs for cancer and autoimmune disorders (therapeutic antibodies) work. The results were published on January 14 in Immunity. In a twist, scientists have known about the molecules involved Read more

Probing visual memory at leisure

"Anecdotally, the paradigm appears to be strikingly less distressing and frustrating to both research participants and clinical patient populations than traditional neuropsychological Read more

Neuro

Insecticide-ADHD link, with caveats

Gary Miller’s lab at Emory was the launching pad for this study from Rutgers, published last week in the FASEB Journal, showing a potential connection between a common type of insecticide used at home and in agriculture, pyrethroids, and attention deficit hyperactivity disorder (ADHD).  Read more

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Point mutation in fragile X gene reveals separable functions in brain

A new paper in PNAS from geneticist Steve Warren and colleagues illustrates the complexity of the protein disrupted in fragile X syndrome. It touches on how proposed drug therapies that address one aspect of fragile X syndrome may not be able to compensate for all of them. [For a human side of this story, read/listen to this recent NPR piece from Jon Hamilton.]

Fragile X syndrome is the most common single-gene disorder responsible for intellectual disability. Most patients with fragile X syndrome inherit it because a repetitive stretch of DNA, which is outside the protein-coding portion of the fragile X gene, is larger than usual. The expanded number of CGG repeats silences the entire gene.

However, simple point mutations affecting the fragile X protein are possible in humans as well. In the PNAS paper, Warren’s team describes what happens with a particularly revealing mutation, which allowed researchers to dissect fragile X protein’s multifaceted functions. Read more

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Effects of cocaine exposure in adolescent rodents

Much of neuroscientist Shannon Gourley’s work focuses on the idea that adolescence is a vulnerable time for the developing brain. She and graduate student Lauren DePoy recently published a paper in Frontiers in Pharmacology showing that in adolescent rodents, cocaine exposure can cause the loss of dendritic arbors in part of the brain important for decision-making.

The researchers examined neurons in the orbitofrontal cortex, a region of the brain thought to be important for “linking reward to hedonic experience.” It was known that stimulants such as cocaine can cause the loss of dendritic spines: small protrusions that are critical for communication and interaction between neurons.

“To make an analogy, it’s like a tree losing some of its leaves,” Gourley writes. “Lauren’s work shows for the first time that if cocaine is given in adolescence, it can cause the loss of dendrite arbors – as if entire branches are being cut from the tree.”

The mice are exposed to cocaine over the course of five days in early adolescence, and then their behavior is studied in adulthood. This level of cocaine exposure leads to impairments in instrumental task reversal, a test where mice need to change their habits (which chamber they poke their noses into) to continue receiving food pellets.

The findings suggest a partial explanation for the increased risk of dependence in people who start using cocaine during adolescence.

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Going meta

Just before Thanksgiving, Slate writer Katy Waldman had a piece summarizing the growing body of evidence that linguistic metaphors reflect how we actually use our brains.

Emory neuroscientist Krish Sathian and his colleagues have been major contributors to this field (“conceptual metaphor theory”). In 2012, he and Simon Lacey published their brain imaging study, which found that when people listened to sentences involving touch metaphors (“having a rough day”), the parts of the brain involved in the sense of touch were activated. NPR’s Jon Hamilton talked about these findings with him in 2013.

At the recent Society for Neuroscience meeting, Sathian discussed his team’s ongoing work on how the brain processes metaphors that make references to body parts (head, face, arm, hand, leg, foot), as part of a nano symposium on language.

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Strategy to defend vs double hit at beginning of life

Chorioamnionitis is a complication of pregnancy: inflammation of the membranes surrounding the fetus, caused by a bacterial infection. It has the potential to inflict damage to the brain of the fetus, especially when combined with fetal hypoxia, and is a known risk factor for developing cerebral palsy.

Chia-Yi (Alex) Kuan and his team, who study fetal brain injury in the Department of Pediatrics, have a new paper in Journal of Neuroscience on a strategy for inhibiting fetal brain inflammation. Postdoctoral fellows Dianer Yang, Yu-Yo Sun and Siddhartha Kumar Bhaumik are co-first authors.

The researchers show that a type of immune cells called Th17 cells seems to be driving inflammation because the rest of the fetal immune system is still immature. A marker of Th17 cells is elevated in blood samples from human infants with chorioamnionitis, the researchers found. Th17 cells are thought to be important for both autoimmunity and anti-microbial responses.

A drug called fingolimod, which stops immune cells from circulating out of the lymph nodes, was effective in reducing inflammation-induced fetal brain injury in animal models. Fingolimod has been approved by the FDA for use with multiple sclerosis and has been studied in clinical trials of kidney transplantation. The authors write that it may be a potential add-on to hypothermia as a treatment for infants in danger of hypoxia + infection-induced brain damage.

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Acidity of aging leads to new Alzheimer’s drug target

Pathologist Keqiang Ye and his colleagues have been studying the functions of an enzyme called AEP, or asparagine endopeptidase, in the brain. AEP is activated by acidic conditions, such as those induced by stroke or seizure.

AEP is a protease. That means it acts as a pair of scissors, snipping pieces off other proteins. In 2008, his laboratory published a paper in Molecular Cell describing how AEP’s acid-activated snipping can unleash other enzymes that break down brain cells’ DNA.

Following a hunch that AEP might be involved in neurodegenerative diseases, Ye’s team has discovered that AEP also acts on tau, which forms neurofibrillary tangles in Alzheimer’s disease.

“We were looking for additional substrates for AEP,” Ye says. “We knew it was activated by acidosis. And we had read in the literature that the aging brain tends to be more acidic, especially in Alzheimer’s.”

The findings, published in Nature Medicine in October, point to AEP as a potential target for drugs that could slow the advance of Alzheimer’s, and may also lead to improved diagnostic tools. Read more

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Explainer: the locus coeruleus

The locus coeruleus is a part of the brain that has been getting a lot of attention recently from Emory neuroscience researchers.

The locus coeruleus is the biggest source of the neurotransmitter norepinephrine in the brain. Located deep in the brainstem, it has connections all over the brain, and is thought to be involved in arousal and attention, stress, memory, the sleep-wake cycle and balance.

Researchers interested in neurodegenerative disease want to look at the locus coeruleus because it may be one of the first structures to degenerate in diseases such as Alzheimer’s and Parkinson’s. In particular, the influential studies of German neuro-anatomist Heiko Braak highlight the locus coeruleus as a key “canary in the coal mine” indicator of neurodegeneration.

That’s why neurologist Dan Huddleston, working with biomedical imaging specialists Xiangchuan Chen and Xiaoping Hu and colleagues at Emory, has been developing a method for estimating the volume of the locus coeruleus by magnetic resonance imaging (MRI). Their procedure uses MRI tuned in such a way to detect the pigment neuromelanin (see panel), which accumulate in both the locus coeruleus and in the substantia nigra. Read more

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Clot dissolver tPA’s tardy twin could aid in stroke recovery

Emory researchers led by neurologist Manuel Yepes, MD have identified a protein released by neurons while the brain is recovering from a stroke. The results were published online today in Journal of Neuroscience.

The protein, called urokinase-type plasminogen activator or uPA, has been approved by the FDA to dissolve blood clots in the lungs. It has been tested in clinical trials in some countries as a treatment for acute stroke.

The Emory team’s findings suggest that in stroke, uPA’s benefits may extend beyond the time when doctors’ principal goal is dissolving the blood clot that is depriving the brain of blood.
Instead, uPA appears to help brain cells recover from the injuries induced by loss of blood flow. Treating mice with uPA after an experimental stroke can improve their recovery of motor function, the researchers found.

Read more

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Revisiting landmark folate-autism study

Geneticist Joe Cubells is doing some monumental work re-examining a Chinese study of folic acid supplementation during pregnancy and its impact on autism risk. He is also the Medical Director at the Emory Autism Center. Please see SFARI to check it out.

 

 

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Many colors in the epigenetic palette

Methylation, an epigenetic modification to DNA, can be thought of as a highlighting pen applied to DNA’s text, adding information but not changing the actual letters of the text.

Are you still with me on the metaphors? If so, consider this wrinkle. (If not, more explanation here.)

Emory geneticist Peng Jin and his colleagues have been a key part of the discovery in the last few years that methylation comes in several colors. His lab has been mapping where 5-hydroxymethylcytosine or 5hmC appears in the genome and inferring how it functions. 5-hmC is particularly abundant in the brain.D5405-2

Methylation, in the form of 5-methylcytosine or 5mC, is both a control button for turning genes off and a sign of their off state. 5hmC looks like 5mC, except it has an extra oxygen. That could be a tag for a removal, or a signal that a gene is poised to be turned on.

Two recent papers on this topic:

Please recall that an enriched environment (exercise and mental stimulation) is good for learning and memory, for young and old. In the journal Genomics, Jin and his team show that exposing mice to an enriched environment  — a running wheel and a variety of toys — leads to a 60 percent reduction in 5hmC in the hippocampus, a region of the brain critical for learning and memory.  The changes in 5hmC were concentrated in genes having to do with axon guidance. Hat tip to the all-things-epigenetic site Epigenie.

In Genes and Development, structural biologist Xiaodong Cheng and colleagues demonstrate that two regulatory proteins that bind DNA (Egr1 and WT1) respond primarily to oxidation of their target sequences rather than methylation. These proteins like plain old C and 5mC equally, but they don’t like 5hmC or other oxidized forms of 5mC. “Gene activity could plausibly be controlled on a much finer scale by these modifications than simply ‘on or ‘off’,” the authors write.

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