Humans respond to a threat with potentially life-saving autonomic responses from the nervous system. “If a bear jumps out at you or you’re crossing a street and a bus almost hits you, you will become rapidly physiologically aroused,” Isaac Galatzer-Levy, lead author of a new study published in Neuropharmacology, tells mental_floss.
How does this happen? Your brain takes in a signal very quickly in the amygdala, which is important for threat detection and response. The hypothalamus releases hormones like epinephrine and norepinephrine, causing you to sweat and your heart to race—preparing you for fight or flight. While this experience may not feel good, it’s “hugely adaptive for your survival,” says Galatzer-Levy, an assistant professor of psychiatry at NYU Langone who specializes in genetic data analysis.
But what if that nervous system response doesn’t go away, even after the immediate threat is long gone? This is what happens in post-traumatic stress disorder (PTSD), which affects about 10 percent of people exposed to traumatic threat. PTSD can bring life-altering symptoms such as intrusive thoughts, sleep problems, depression, and anxiety.
Recently, researchers discovered a new way to potentially treat PTSD with a drug that manipulates the expression of the gene FKBP5, which is associated with PTSD (as well as with schizophrenia and depression). Most animals have FKBP5, as does every human—but there are different versions of it. Scientists have discovered that several variants of the gene, known as RS9470080 and RS1360780, are linked to PTSD. The FKBP5 gene signals to the brain through a protein it produces, which helps cortisol to bind to the receptors in the brain; this allows your nervous system to calm down after a stressful event.
Depending on the variant of the gene that you have, your brain may produce more or less of the protein. Those with more of the protein, it turns out, tend to have a lower risk of PTSD symptoms after trauma.
WHEN FEARS WON'T GO "EXTINCT"
With the current study, Galatzer-Levy wanted to know if genetic factors increase the risk of "abnormal fear learning and fear extinction"—that is, how people learn to connect events with danger, and how well these connections can be unlearned. He reanalyzed data from studies conducted at Emory University on fear conditioning and fear extinction. He wanted to determine if the variant of FKBP5 also changed how people learned to be afraid, and if that is linked to stress pathology. “We found it was," he says. "Abnormal fear extinction patterns are associated with hyper arousal.”
To make that determination, Galatzer-Levy pooled data from a series of studies where participants in various research projects went through fear condition and fear extinction testing; altogether, Galatzer-Levy looked at 724 people's responses. All subjects had completed at least three conditioning tests and four extinction tests, and had contributed saliva for genetic testing to determine if they had the variant of FKBP5.
Many of the conditioning tests involved a blast of air to the larynx, which triggers an automatic eye blink startle response faster than the mind can process what has happened. Galatzer-Levy says it takes approximately 30 blasts for people to start wincing at the orange circle, even in the absence of an air blast.
Once they were fear conditioned, researchers attempted to extinguish the learned fear—subjects were shown the circle with no blasts of air, until they stopped wincing at the sight of the orange circle. Galatzer-Levy's review found that there was an connection between having the gene variant and having difficulty extinguishing fear.
TESTING THE IMPACT OF A COMMON STEROID
In the animal study, the researchers set out to see if they could manipulate this fear extinction pattern in mice by administering a commonly prescribed steroid, dexamethasone, shown to help prevent symptoms of PTSD.
Scientists put 124 mice through fear conditioning by pairing a shock with a light approximately 50 times in one session. “This develops the association so the light comes to represent the shock. The animal starts responding to the light the way they do the shock,” Galatzer-Levy describes. Then, a day after the mice were fear conditioned, the researchers dosed them with enough dexamethasone to pass the blood brain barrier, about 300 micrograms in a systemic injection (as opposed to injecting it directly into the amygdala). They wanted to know if the steroid would alter the consolidation of the memory that paired the shock and the light.
Indeed, when they gave dexamethasone to the mice with trouble extinguishing fear, the amygdala produced a lot of the FKBP5 protein, and the animals stopped exhibiting fear responses in subsequent tests.
“This showed that gene really does confer risk in abnormal patterns of learning and then PTSD psychopathology,” Galatzer-Levy says.
THE NEXT STEP: PILOTING THE DRUG IN AN EMERGENCY ROOM
He’s aware that this kind of research can sound very “deterministic,” but is quick to point out simply having the gene variant isn’t enough to guarantee you will develop PTSD—in fact, since intervention appears to be possible, it may help identify those at risk so they can get treatment. “If we can manipulate the expression of the gene during the critical window of memory formation, then we can potentially prevent those deficits in fear extinction,” Galatzer-Levy says.
Since it’s obviously unethical to shock humans the same way they did with the mice, Galatzer-Levy is now conducting a pilot trial in conjunction with the emergency department at Bellevue Hospital in New York. Willing participants admitted to the hospital for traumas—ranging from car accident to assault—will receive a single dose of dexamethasone within the first couple of hours following their traumatic event. “The drug is already in common use, it’s generic, and generally safe. It’s a good choice as an early intervention in an emergency setting,” he explains. It's open label, which means that participants aren’t blind to what they’re getting, and there is no placebo control.
To move to that next stage of trial will require more funding, but he’s optimistic. As the research moves forward, Galatzer-Levy is hopeful that the results will offer a simple solution for those who suffer from PTSD.