Fight or flight, panic, trembling: Our brains are wired to ensure we respond instantly to fear. While that fear response may save our lives in the dangerous moment, at times people stay on high alert long after the threat has passed, and develop post-traumatic stress disorder.
A new study from Scripps Research suggests it may be possible to disarm the emotional memories of trauma that drive PTSD symptoms by targeting a molecule found elevated within the brain’s emotional memory processor, the amygdala. The research also may offer a novel biomarker for treatment.
Writing in the journal Molecular Psychiatry, Scripps Research neuroscientist Courtney Miller, PhD,and her team describe mir-135b-5p, a microRNA in the basolateral amygdala complex, where long-term memories of fear reside. They found the microRNA altered in both stress-conditioned mice and in military veterans who had been diagnosed with PTSD following deployment in Afghanistan.
“There are limited options for people with PTSD,” Miller says. “We asked whether we could identify something unique to the storage of traumatic memories to get at the heart of the problem.”
About 10 percent of women and 4 percent of men will experience post-traumatic stress disorder at some point in their lives, putting them at risk for depression and drug addiction, with rates even higher in the military. An estimated 8 million people a year in the United States cope with the disorder. Sleep, thinking, relationships and jobs frequently suffer.
“The main medications used to treat PTSD are selective serotonin reuptake inhibitors, or SSRIs. They can help symptoms, but for many, they don’t help enough,” Miller says. “There’s nothing available that targets the traumatic memories themselves.”
In prior work, Miller has developed a potential drug that disrupts long-term methamphetamine-associated emotional memories as a strategy for prevention of relapse in drug addiction. That success convinced her that it might also be possible to disrupt long-term emotional memories specific to PTSD.
Within cells, microRNA molecules serve to regulate how genes are expressed. More than 2,000 different types of microRNAs have been identified recently. Discoveries from Scripps Research and elsewhere have shown it’s possible to design drug molecules to regulate them as a way of treating diseases once thought undruggable.
“We chose to focus on microRNAs because of their ability to titrate the expression of many molecules involved in memory, not just one, and we focused on microRNAs expressed specifically under conditions of stress susceptibility to avoid wiping out people’s memories in general,” Miller explains.
Her group worked first with stress-conditioned mice to identify microRNA unique to those who appeared permanently changed by their stress exposure. The mouse research revealed mir-135b-5p as a key differentiator between stressed and resilient mice. Next, they exposed mice to stress conditioning and then silenced mir-135b-5p. Those without the microRNA proved uncommonly resilient.
Working with brain tissue samples from the Harvard Medical School Department of Psychiatry, Miller’s group found that the microRNA was also conserved from mouse to humans. Next, they identified a consortium in the Netherlands that had collected blood samples six months after Dutch military veterans had served in Afghanistan conflict zones for four-month tours. Some had been diagnosed with PTSD.
In the serum from the PTSD group, they likewise found selective elevation of mir-135b’s “passenger” strand.
Looking ahead, Miller wants to explore how time course may affect response to treatment, and how gender differences may involve alternate traumatic memory storage mechanisms. The data from mice suggested a different mechanism was at work in the females, she says.
“I’m excited about the potential of this as a therapeutic target,” Miller says. “The passenger strand may be a biomarker of responsivity to a mir-135-based therapeutic.”
In addition to Miller, the authors of “MicroRNA regulation of persistent stress-enhanced Memory,”published online May 29, 2019 in the journal Molecular Psychiatry, are: First author Stephanie Sillivan, Sarah Jamieson, Megan Jones, Nadine Joseph and Gavin Rumbaugh of Scripps Research; Laurence de Nijs, Clara Snijders, Bart Rutten, Julian Krauskopf and Jos Kleinjans of Maastricht University in The Netherlands; Torsten Klengel and Kerry Ressler of the Harvard Medical School Department of Psychiatry; Christiaan Vinkers, Marco Boks, Elbert Geuze and Eric Vermetten of the University Medical Center Utrecht Department of Psychiatry Rudolf Mangus Brain Center in The Netherlands.
The work was funded by grants from the National Institute of Mental Health MH105400 and MH105400-02 (Diversity Supplement) (CM), National Institute of Neurological Disorders and Stroke NS096833 (CM), National Institute on Drug Abuse DA041469 (SS) and the Brain and Behavior FoundationNARSAD Young Investigator Award (SS). This research project was also supported in part by the Viral Vector Core of the Emory Neuroscience National Institute of Neurological Disorders and Stroke Core Facilities grant, P30NS055077. LdN and smRNA-Seq experiments in human serum were funded by a VIDI award number 91718336 from the Netherlands Scientiﬁc Organization (BR) and the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 707362 (LDN).