How stress turns into fear

It’s normal to feel stressed when faced with a challenge or fearful when faced with a threat. This innate survival mechanism allows us to remain vigilant and avoid danger (or run away). But when fear is constant and meaningless, there is a risk of slipping into disorders such as anxiety, phobias, depression, post-traumatic stress syndrome (PTSD), etc. How does this shift occur? Although we have long been aware of certain areas of the brain that are responsible for negative emotions, such as the amygdala and the “biological stress axis”, which allows our body to react in case of difficulties, in particular through the secretion of cortisol. the processes involved in the transformation of stress into persistent fear remained unknown. Since then, Hui-quan Li and his colleagues at the University of California, San Diego have begun to discover these “fear neurons”…

To do this, they worked with mice, which, like us, can develop a form of post-traumatic stress disorder. By regularly being subjected to electric shocks in a certain compartment of their cage, they eventually become “fear conditioned”: they associate pain with that place and systematically begin to experience stress while being there, even without experiencing any shocks. Moreover, if at the moment of conditioning the electric shocks are very intense, rodents are afraid even in a place different from where they received them, although they are not afraid of anything! So the animals developed what we call “generalized fear,” similar to post-traumatic stress disorder. What happened in their brains?

Changes in neurotransmitters in the “schwa”

Previous research has shown that intense fear, such as a panic attack, corresponds to the activity of certain neurotransmitters—molecules that communicate between neurons—in the nuclear circuits of a nerve region called the “dorsal raphe,” located below the brain stem; more specifically, it is the activity of serotonin-secreting neurons that is associated with panic behavior. However, the latter are also capable of co-releasing another molecule, GABA, the brain’s main inhibitory neurotransmitter, or even glutamate, the most common excitatory neurotransmitter. What did the researchers notice two weeks after the electric shock, when the mice developed generalized fear?

A form of cerebral plasticity: in response to acute and severe stress rather than mild stress, serotonergic neurons in the raphe nuclei change most of their “cotransmitters,” this time secreting more GABA than glutamate (without changing the total number of neurons). ). The latter have also been linked to other areas of the brain that we know are involved in fear, such as the amygdala. Moreover, to prove that electric shock actually triggers neuronal plasticity by stimulating the body’s stress axis and the secretion of glucocorticoids (including cortisol), the receptors of which are located in the dorsal raphe, the researchers administered cortisone to rodents that had received only mild electric shocks: These animals then developed a generalized fear, as if they had been exposed to a strong stimulus, with transformation of raphe neurons. Finally, similar changes were observed in the same neurons in people who died from post-traumatic stress disorder…

Can we prevent this switching of serotonergic neurons and the emergence of generalized fear in rodents? Yes, the researchers achieved this by blocking either the conversion of serotonergic raphe neurons or their glucocorticoid receptors in mice. But also by giving them fluoxetine, an antidepressant, as long as it is done within four weeks of developing generalized fear – while plasticity remains after the electric shock. Moreover, the treatment was ineffective. However, in humans this period corresponds to approximately three years, which arguably represents the time before severe stress can transform into trauma. Therefore, the researchers suggest that the emergence of irrational fear could be avoided if the subjects were quickly helped after a stressful event.