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Fear arises from chemical changes deep in the brain

A study with mice and post-mortem human tissues shows how generalized fear can occur even in the absence of objective threats

Miedo
A new study published in 'Science' identified the biochemistry of the brain and the neural circuits that trigger generalized fear.Spitzer Lab, UC San Diego
Miguel Ángel Criado

Without fear, the evolution of life would have been impossible. Any threat triggers states of alarm that protect through two alternative reactions, flight or fight. Present throughout human history, in advanced modern societies the situations in which it appears are reduced to extremes such as personal violence (rape, robbery, kidnapping) or collective violence (war, civil conflict). In people with post-traumatic stress disorder, this dread often reappears even when there is no longer a threat. Now, a group of scientists has discovered what happens in the brain to cause the distress to return. In the future, this could be the basis for a drug therapy against fear.

Based on what is known about conditioned fear, based on a real threat, researchers at the University of California, San Diego sought the chemical basis of generalized fear, in which there is no objective situation of danger. To do so, they studied the parts of the brain involved in this state, in particular two regions of the brain stem at the base of the brain (the periaqueductal gray and the dorsal raphe nucleus). They did this in mice, a model that allows extrapolations to human organs. In these regions there are clusters of serotonergic neurons that, by releasing this neurotransmitter, regulate an infinite number of basic processes, such as states of alertness and wakefulness, hunger, fear.... What they did was to observe the activity in these neuronal areas while performing a series of experiments in which they subjected rodents to shocks of different intensities on their paws.

“We discovered that after acute stress, certain nerve cells in the dorsal region of the raphe change the molecules (neurotransmitters) they use to send signals to other nerve cells,” explains Kavli Institute for Brain and Mind researcher and senior author of this research, Nick Spitzer. Specifically, they saw a change in the neurotransmitters released by the neurons, changing one of them, glutamate, to another one called γ-aminobutyric acid and known by its acronym, GABA. “This change causes these neurons to inhibit the cells they make connections with, rather than excite the cells they make connections with,” he adds. The consequence of this reversal of signaling is that “the mice had generalized fear, to environments other than the one in which they experienced the acute stress.”

The research, published in the scientific journal Science, went a step further by looking for a correlate in humans. To do so, the researchers analyzed samples from a dozen deceased people, half of them with post-traumatic stress disorder (PTSD) and the others as a control group. They found that the brain stem tissues of the individuals with PTSD showed a marked decrease in the number of neurons that, in addition to serotonin, expressed glutamate. Specifically, up to 26.12% and, in parallel, a reduced increase of only 6.5% of those co-expressing serotonin and GABA. The authors emphasize that many more studies will have to be done, with larger samples, but the replication in humans (although with tissues in the laboratory), led them to seek how to block this exchange of neurotransmitters.

Then they went back to the mice. The researchers found a way to stop the production of this generalized fear. To do this, before the mice were hit on the paws and thus experienced acute stress, they injected into the dorsal raphe of a group of rodents an adenovirus to suppress the gene responsible for the synthesis of the neurotransmitter GABA. They succeeded in preventing the mice from acquiring generalized fear.

“But most exciting was the discovery that immediate administration of an antidepressant drug, fluoxetine, succeeded in preventing the change in signaling molecules, thus preventing the onset of generalized fear in mice,” Spitzer emphasizes. Fluoxetine is the active ingredient of a famous drug, Prozac. What they found is that the mice that received an injection of this drug just after the shocks not only had that exchange of glutamate for GABA, but did not become paralyzed in the different situations in which they were placed to induce fear. What could this mean? “This research raises the possibility of quickly administering fluoxetine to people after a very bad and terrifying experience, to prevent them from acquiring generalized fear,” concludes the American neuroscientist.

The head of the Neurology department at the 12 de Octubre University Hospital in Madrid, Alberto Villarejo, emphasizes that this is basic science research. “Fear is a physiological protective mechanism of animals and humans in the face of a threat,” he underscores. But on certain occasions and in certain people, “this complex mechanism is triggered in situations that are not really threatening.” And we don’t know why. Cultural differences intervene. “Poverty and the fear of it generates more anxiety in countries like the United States than in others where material things are not so highly valued,” notes Villarejo. The personality of each individual also plays a role, how they deal with problems. Another element is the possible genetic influence and, finally, the neuronal connections through neurotransmitters.

The most extreme cases are those tied to post-traumatic stress disorder caused by situations of extreme violence such as terrorist attacks or wars. “That’s when this generalized fear can emerge, triggered by unrelated stimuli,” says Villarejo, who notes that Prozac is already being used as treatment, but that “psychotherapy remains fundamental.”

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