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 typeÂ 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.
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 AEPâ€™s acid-activated snipping can unleash other enzymes that break down brain cellsâ€™ DNA.
Following a hunch that AEP might be involved in neurodegenerative diseases, Yeâ€™s team has discovered that AEP also acts on tau, which forms neurofibrillary tangles in Alzheimerâ€™s disease.
â€œWe were looking for additional substrates for AEP,â€ Ye says. â€œWe knew it was activated by acidosis. And we had readÂ in the literature that the aging brain tends to be more acidic, especially in Alzheimerâ€™s.â€
The findings, published in Nature Medicine in October, point to AEP as a potential target for drugs that could slow the advance of Alzheimerâ€™s, and may also lead to improved diagnostic tools. Read more
The locus coeruleus is a part of the brain that has been getting a lot of attention recently from Emory neuroscienceÂ 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 Alzheimerâ€™s and Parkinsonâ€™s. In particular, the influential studies of German neuro-anatomist Heiko Braak highlight the locus coeruleus as a key â€œcanary in the coal mineâ€ indicator of neurodegeneration.
Thatâ€™s why neurologist Dan Huddleston, working with biomedical imaging specialists Xiangchuan Chen and Xiaoping Hu and colleagues at Emory, hasÂ 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), whichÂ accumulate in both theÂ locus coeruleus and in the substantia nigra. Read more
Emory researchers led by neurologist Manuel Yepes, MD have identified a protein released by neurons while the brain is recovering from a stroke.Â The results were published online today inÂ 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 trialsÂ in some countriesÂ as a treatment for acute stroke.
The Emory teamâ€™s findings suggest that in stroke, uPAâ€™s benefits may extend beyond the time when doctorsâ€™ 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.
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.
Methylation, an epigenetic modification to DNA, can be thought of as a highlighting pen applied to DNAâ€™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.
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 aÂ 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 journalÂ Genomics, Jin and his team show that exposing mice to an enriched environmentÂ — 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. Â The changes in 5hmC were concentratedÂ 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 demonstrateÂ 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 donâ€™t like 5hmC or other oxidized forms of 5mC. â€œGene activity could plausibly be controlled on a much finer scale by these modifications than simply â€˜on or â€˜offâ€™,â€ the authors write.
Iâ€™d like to highlight a paper in PLOS One from anesthesiologists Shan Ping Yu and Ling Weiâ€™s group that was published earlier this year. [Sorry for missing it then!] They are investigating potential therapies for stroke, long a frustrating area of clinical research. The â€œclot-bustingâ€ drug tPA remains the only FDA-approved therapy, despite decades of work on potential neuroprotective agents.
Yuâ€™s team takes a different tactic. They seek to bolster the brainâ€™s recovery powers after stroke by mobilizing endogenous progenitor cells. I will call this approach â€œstem cells lite.â€
PTH appears to encourage new neurons in recovery in a mouse model of ischemicÂ stroke. Green = recent cell division, red = neuronal marker
It is similar to that taken by cardiologistÂ Arshed Quyyumi and colleagues with peripheral artery disease: use a growthÂ factorÂ (GM-CSF), which is usually employed for another purpose, to get the bodyâ€™s own regenerative agents to emerge from the bone marrow.
In this case, Yuâ€™s team wasÂ using parathyroid hormone (PTH), which is an FDA-approved treatment for osteoporosis. They administered it, beginning one hour after loss of blood flow, in a mouse model of ischemic stroke. They foundÂ that daily treatment with PTH spurs production of endogenousÂ regenerative factors in the stroke-affected area of the brain. They observed both increased new neuron formation and sensorimotor functional recovery. However, PTH does not pass through the blood-brain barrier and does not change the size of the stroke-affected area, the researchers found.
The conclusion of the paper hints at their next steps:
As this is the first report on this PTH therapy for ischemic stroke for the demonstration of the efficacy and feasibility, PTH treatment was initiated at 1 hr after stroke followed by repeated administrations for 6 days. We expect that even more delayed treatment of PTH, e.g. several hrs after stroke, can be beneficial in promoting chronic angiogenesis and other tissue repair processes. This possibility, however, remains to be further evaluated in a more translational investigation.
In contrast to evidence that the amygdala stimulates stress responses in adults, researchers at Yerkes National Primate Research Center, Emory University have found that the amygdala has an inhibitory effect on stress hormones during the early development of nonhuman primates.
The results are published this week in Journal of Neuroscience.
The amygdala is a region of the brain known to be important for responses to threatening situations and learning about threats. Alterations in the amygdala have been reported in psychiatric disorders such as depression, anxiety disorders like PTSD, schizophrenia and autism spectrum disorder. However, much of what is known about the amygdala comes from research on adults.
â€œOur findings fit into anÂ emerging themeÂ in neuroscience research: that during childhood, there is a switch in amygdala function and connectivity with other brain regions, particularly the prefrontal cortex,â€ says Mar Sanchez, PhD, neuroscience researcher at Yerkes and associate professor of psychiatry and behavioral sciences at Emory University School of Medicine. The first author of the paper is postdoctoral fellow Jessica Raper, PhD.
Some notableÂ links on the amygdala:
*AnÂ effort to correctÂ simplistic views of amygdala as the “fear center” of the brain
*Collection of papers mentioningÂ patient SM, an adult human with an amygdala lesion
*Recent Nature Neuroscience paper on amygdala’s role in appetite control
*Evidence for changing amygdala-prefrontal connectivity in humansÂ during development Read more