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

CRF

Neurosurgery via genetics to modulate anxiety

If you hear someone talking about a stress hormone, they’re probably talking about cortisol. It’s released by the adrenal glands in stressful situations, whether you have to escape a bear or just give a speech. Cortisol is supposed to prepare the body for “fight or flight.”

Kerry Ressler, MD, PhD

Let’s step back a bit, and look at how the brain triggers cortisol production: through a peptide produced in the brain called CRF (corticotropin-releasing factor). CRF is elevated in several disorders such as depression and PTSD, and is also thought to be involved in drug and alcohol dependency.

Neurons that make CRF are found in locations all over the brain, so studying them can be tricky. Kerry Ressler and his colleagues have developed an intriguing tool for studying CRF. In the places where CRF is produced in a mouse’s brain, they can take out the gene of their choice.

Green spots (above) and blue staining (below) indicate where CRF is produced in the mouse brain.
PVN = hypothalamus, paraventricular nucleus
CeA = central amygdala

In a new paper in PNAS, postdoc Georgette Gafford and Ressler use this tool in a subtle way. They have mice where a gene for a GABA receptor, one of the main inhibitory receptors (brakes) in the nervous system, is deleted, but only in the CRF neurons. This basically has the effect of turning up the volume on CRF production in several parts of the brain. It appears that modulating GABA receptors is something that normally happens to regulate CRF production, but in this case, a restraint on these stress-sensitive cells has been taken off.

“These mice are normal in many ways – normal locomotor and pain responses and no difference in depressive-like behavior or Pavlovian fear conditioning. However, these mutants have increased anxiety-like behavior,” Gafford and Ressler write.

They also have “impaired extinction of conditioned fear,” meaning that they have trouble becoming NOT afraid of something, like a buzzing sound, to which they have been sensitized by shocks. This is analogous to PTSD in which patients remain afraid and aren’t able to successfully inhibit their prior fear learning, even after the context is now safe.  [A 2011 paper goes into more detail on this biological aspect of PTSD in a civilian population.]

“These data indicate that disturbance of this specific population of neurons causes increased anxiety and impaired fear extinction, and helps us to further understand mechanisms of fear- and anxiety-related disorders such as PTSD,” Ressler and Gafford write.

In the mutant mice, a drug that blocks CRF rescued their behavioral impairments. Some other recent investigations of mice with CRF overproduction in the brain revealed “surprising paradoxical effects.”

Drugs that block CRF have been in clinical trials, some with mixed results.  A trial now proceeding at Emory is evaluating a CRF antagonist in women with PTSD.

Ressler, associate professor of psychiatry and behavioral sciences, is a Howard Hughes Medical Investigator, with a laboratory at the Yerkes National Primate Research Center. He is also co-director of the Grady Trauma Project.

 

 

Posted on by Quinn Eastman in Neuro Leave a comment