The stress-induced mechanisms that lead our brain to develop feelings of dread in the absence of dangers, such as in PTSD, remain largely unknown. Neurobiologists have now pinpointed the biochemical changes in the brain and delineated the neural circuitry responsible for generalized fear feelings.
Our neurological systems are innately wired to detect fear. Our fear reaction, whether triggered by creepy noises we hear alone in the dark or the approaching growl of a deadly animal, is a survival strategy that instructs us to stay vigilant and avoid risky circumstances.
However, when fear occurs in the absence of concrete threats, it can be detrimental to our well-being. Those who have experienced episodes of acute or life-threatening stress may later experience intense sensations of terror, even in settings where there is no real threat. This generalization of fear is psychologically harmful and can lead to debilitating long-term mental health issues like post-traumatic stress disorder (PTSD).
Our results provide important insights into the mechanisms involved in fear generalization. The benefit of understanding these processes at this level of molecular detail – what is going on and where it’s going on – allows an intervention that is specific to the mechanism that drives related disorders.
Dr. Spitzer
The stress-induced mechanisms that cause our brain to develop sensations of dread in the absence of a threat remain largely unknown. Neurobiologists at the University of California, San Diego, have identified the alterations in brain biochemistry and mapped the neural circuitry that create such a widespread dread experience. Their research, published in the journal Science, provides new insights into how fear responses could be prevented.
In their report, former UC San Diego Assistant Project Scientist Hui-quan Li, (now a senior scientist at Neurocrine Biosciences), Atkinson Family Distinguished Professor Nick Spitzer of the School of Biological Sciences and their colleagues describe the research behind their discovery of the neurotransmitters — the chemical messengers that allow the brain’s neurons to communicate with one another — at the root of stress-induced generalized fear.
Studying the brains of mice in an area known as the dorsal raphe (located in the brainstem), the researchers found that acute stress induced a switch in the chemical signals in the neurons, flipping from excitatory “glutamate” to inhibitory “GABA” neurotransmitters, which led to generalized fear responses.
“Our results provide important insights into the mechanisms involved in fear generalization,” said Spitzer, a member of UC San Diego’s Department of Neurobiology and Kavli Institute for Brain and Mind. “The benefit of understanding these processes at this level of molecular detail — what is going on and where it’s going on — allows an intervention that is specific to the mechanism that drives related disorders.”
Building upon this new finding of a stress-induced switch in neurotransmitters, considered a form of brain plasticity, the researchers then examined the postmortem human brains of individuals who had suffered from PTSD. A similar glutamate-to-GABA neurotransmitter switch was confirmed in their brains as well.
The researchers then discovered a strategy to prevent the development of generalized dread. Before the mice experienced acute stress, they injected an adeno-associated virus (AAV) into their dorsal raphe to repress the gene responsible for GABA production. This method stopped the mice from developing generalized fear.
Furthermore, when mice were given the antidepressant fluoxetine (brand name Prozac) right after a stressful incident, the transmitter switch and the subsequent induction of generalized dread were averted.
The researchers not only identified the neurons that flipped their transmitter, but they also revealed connections between these neurons and the central amygdala and lateral hypothalamus, brain regions previously related to the development of other fear reactions.
“Now that we have a handle on the core of the mechanism by which stress-induced fear happens and the circuitry that implements this fear, interventions can be targeted and specific,” said Spitzer.
