Scientists have discovered that resident bacteria of the intestine, collectively known as the gut microbiome, can influence the ability to overcome fear.
The finding, published in the journal Nature, could one day help people with post-traumatic stress disorder. It also dramatically expands understanding of the “gut-brain” axis, which is known to have a hand in depression, anxiety and autism.
The researchers, led by immunologist David Artis at Cornell University in New York, US, started by putting the frighteners on a bunch of mice – some healthy and others treated with antibiotics to wipe out their gut bacteria.
They followed standard procedure for getting mice scared. They put the critters in a special chamber where a tone sounded for 30 seconds. When the tone stopped the mice got an electric shock to their feet through the floor.
As you might expect, it wasn’t long before they started freezing with fear as soon as they heard the tone – your paradigm case of Pavlovian conditioning.
Fortunately for mice, however, fear can be unlearned.
In the best of all possible worlds, when the tone is sounded later without the shock, mice will eventually stop freezing when they hear it. Which is exactly what happened to the normal mice. But the antibiotic-treated mice just couldn’t stop freezing to the tone, long after the shocks had stopped.
Now that sounds a lot like returned soldiers who can’t dial down the fear when a helicopter flies overhead or they walk down an eerily empty street, just a couple of potential triggers for post-traumatic stress.
Which is all the more reason to find out why those mice without microbes were so bad at unlearning fear.
The researchers started working through their suspect list.
They began with the vagus nerve, which is something of a signalling superhighway between the gut and the brain. But when they cut the vagus nerve in the mice with no germs, it made no difference.
So they turned to the immune system, known to play a role in brain function, and re-ran the experiment in mice bred to lack a special type of immune cell. It had no effect.
Then they ratcheted things up and looked at gene expression in the brains of those impaired mice. They were getting warm. The mice had big changes in the genes of several different brain cell types.
Could those genes, they wondered, be rewiring the brain in a bad way? To find out, they used a technique called two photon imaging to peer into the skulls of the live mice and map their brain structure, right down to the level of individual neurons.
Those challenged mice, it turned out, had a defect in their ability to rewire two parts of the brain – the amygdala and the medial prefrontal cortex – that are crucial for extinguishing fear.
But how, precisely, could bacteria way down in the gut alter the anatomy of a brain perched on high?
The team narrowed their focus to four metabolites of gut bacteria known to circulate in the cerebrospinal fluid that bathes the brain. Levels of all four, they discovered, were way down. Two of those metabolites are linked to schizophrenia and autism in humans.
It would appear they had their smoking gun.
“[O]ur findings offer one compelling explanation for the notable deficits in fear extinction learning in [antibiotic-treated mice]… and suggest that alterations in microbiota-derived metabolites contribute to altered neuronal activity and behaviour,” they conclude.
In a commentary on the article, psychiatrist and neuroscientist Drew Kiraly from the Icahn School of Medicine at Mount Sinai in New York City, spells out what this could mean for people.
“Perhaps most germane to the current study would be the treatment of post-traumatic stress disorder, in which people cannot extinguish memories of frightening or traumatic experiences,” he writes.
“[This] work raises the possibility of targeting the gut microbiota and its metabolites as a strategy for helping such individuals.”
Paul Biegler is a philosopher, physician and Adjunct Research Fellow in Bioethics at Monash University. He received the 2012 Australasian Association of Philosophy Media Prize and his book The Ethical Treatment of Depression (MIT Press 2011) won the Australian Museum Eureka Prize for Research in Ethics.
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