How Stress Turns into Fear in the Brain

Our fear response is a survival mechanism that signals us to remain alert and avoid dangerous situations. Those who have suffered episodes of severe or life-threatening stress can later experience intense feelings of fear, even during situations that lack a real threat. Experiencing this generalization of fear is psychologically damaging and can result in conditions such as post-traumatic stress disorder (PTSD). The stress-induced mechanisms that cause our brain to produce feelings of fear in the absence of threats has not been fully understood. Now, neurobiologists at the University of California (UC), San Diego, have identified the changes in brain biochemistry and mapped the neural circuitry that cause such a generalized fear experience.

The findings are published in Science in an article titled, “Generalized fear after acute stress is caused by change in neuronal co-transmitter identity.”

“Overgeneralization of fear to harmless situations is a core feature of anxiety disorders resulting from acute stress, yet the mechanisms by which fear becomes generalized are poorly understood,” the researchers wrote. “In this study, we show that generalized fear in mice results from a transmitter switch from glutamate to γ-aminobutyric acid (GABA) in serotonergic neurons of the lateral wings of the dorsal raphe. A similar change in transmitter identity was found in the postmortem brains of individuals with post-traumatic stress disorder (PTSD). Overriding the transmitter switch in mice prevented the acquisition of generalized fear.”

In their research, former UC San Diego assistant project scientist Hui-quan Li, PhD, (now a senior scientist at Neurocrine Biosciences), Nick Spitzer, PhD, the Atkinson Family Distinguished Professor of the School of Biological Sciences, and their colleagues described 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.

The researchers studied the brains of mice in an area known as the dorsal raphe, and discovered 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, who is also a member of UC San Diego’s department of neurobiology and the 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.”

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 found a way to block the production of generalized fear. Prior to the experience of acute stress, they injected the dorsal raphe of the mice with an adeno-associated virus (AAV) to suppress the gene responsible for synthesis of GABA. This method prevented the mice from acquiring generalized fear.

Further, when mice were treated with the antidepressant fluoxetine (branded as Prozac) immediately after a stressful event, the transmitter switch and subsequent onset of generalized fear were prevented.

Not only did the researchers identify the location of the neurons that switched their transmitter, but they demonstrated the connections of these neurons to the central amygdala and lateral hypothalamus, brain regions that were previously linked to the generation of other fear responses.

“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.