Neuroscientist Ki Goosens does her research with black and white rats, but what she has discovered could be very relevant to humans — including her own family.
In the last eight years, three family members have become suicidal in the wake of a “major life stressor” like divorce.
“For years, they were fine, and then it triggers some cascade of vulnerability,” she said. “So I feel a sense of urgency in trying to come up with new ways to think about how we can block the ability of stress to worsen mental illness, to trigger mental illness.”
Goosens and her team at MIT’s McGovern Institute for Brain Research have just published what could be a major lead: A hormone called ghrelin — known as the hunger hormone and made in the stomach — may be a key to post-traumatic stress disorder and other stress-related mental illnesses.
The research is still early, but it raises the possibility that drugs that block ghrelin could be used to block some of the mental harm done by chronic stress.
Goosens and her collaborators at Mass. General Hospital are now planning two studies on ghrelin in humans: One will determine whether ghrelin levels are elevated in people with anxiety disorders; the other will block ghrelin signaling in hopes of preventing stress-related relapses of depression.
Goosens never expected to be using a hunger hormone to understand stress: “If you had asked me five years ago if I would be doing something related to the stomach, I would’ve said, ‘No way, you’re crazy. I’m a neuroscientist! I study the brain,’” she said. “But you sort of go where the data take you.”
She originally set out to explore how stress affects the activity of genes in the amygdala, a part of the brain that processes emotions.
She found that when chronic stress was high, so were ghrelin levels. And unlike the hormones we usually think of as stress-related, like adrenaline, which peak and then drop quickly, the ghrelin would go up and stay up for weeks or months.
For decades, scientists have naturally expected stress hormones to be the source of stress-related mental illnesses, like PTSD. But a stomach hormone? Why would a hunger hormone be a key player in stress and fear?
Goosens obligingly speculated: “I’ve thought a lot about this,” she said. “In some ways, you can think of all organisms as just complicated food tubes, right? Most of our body is in fact a digestive tract, and our brain controls our access to food. I think probably the most primordial type of stress, that applies to humans but also to single-celled organisms, is starvation, where you don’t have enough food. And it’s when you’re starving, when your stomach is empty, that your body will produce ghrelin.
“And so what I’m thinking is that perhaps ghrelin represented a very primordial type of stress, starvation, and that over time, our brains have co-opted that signal, and use it to indicate more than just starvation — that it’s a broader indicator of other types of stress.”
Goosens began testing her ghrelin hypothesis in her lab’s rats. She kept some happy, “control” rats, unbothered in their little plastic boxes, and then there were the chronically stressed rats: For a couple of hours every day, they would be brought down to the lab and put into clear plastic bags that limited their movement — the equivalent of a straitjacket for a rat.
They were not in pain; they just couldn’t move. But they hated it. It cast them into a state of psychological stress.
After the rats had been stressed for a week or more, they and the happy control rats were taught to fear a tone: Every time they heard it, they got a tiny foot shock. Soon, just hearing the tone was enough to make the rats freeze in fear.
How long they froze showed how strong their fear was — and the rats who were chronically stressed tended to freeze at the sound of the tone for a much longer time than the unstressed rats. So they were reacting to a perceived threat something like humans with PTSD.
Next, Goosens and her student Retsina Meyer — now a new-minted MIT PhD — injected the unstressed rats repeatedly with a ghrelin activator. That made the unstressed rats freeze in reaction to the tone longer, just like the stressed rats.
Then, Goosens and her team tried the opposite experiment: They took the chronically stressed rats and blocked their ghrelin receptors. Now, “when you expose them to the fear conditioning, they don’t have the enhanced fear,” she said. “They behave as though they were unstressed animals.”
Goosens has even tried removing rats‘ adrenal glands — the source of stress hormones like adrenaline and cortisol — and found that chronic stress still raises ghrelin levels and enhances the rats’ fear response. So ghrelin seems to be a truly novel pathway, independent of those classic stress hormones.
She and her team published their findings last week.
Dr. Bruce McEwen of Rockefeller University, a leading researcher on the effects of stress on the brain, says the ghrelin paper is credible work that “extends our knowledge of molecular players in fear that is certainly relevant to PTSD.”
It “opens an avenue that’s well worth studying,” he said.
After ghrelin was discovered in the 1990s, some researchers figured that if ghrelin makes you hungry, then maybe drugs to block it could help people lose weight. The drugs they developed were mostly safe — the only problem was, they didn’t work for weight loss.
Ki Goosens is hoping that now, those ghrelin-blocking drugs will find a new use: “It’s really exciting to think about all these drugs that might be, in fact, repurposed to target PTSD or other stress-sensitive mental disorders,” she said.
She knows, from her own family’s experience, how great the need is for better psychiatric drugs. She has seen her brother continue to struggle after his divorce brought on a breakdown.
“I know that stress was a major factor in his illness, and so that changed the way I thought about my own research,” she said. “Instead of just doing research to publish exciting papers and add knowledge to textbooks, as admirable as I think that is, I just decided that I really wanted to do research that would have a tangible impact in people’s lives.”