The human nervous system is designed to detect fear when something in the environment seems unsettling or threatening, such as noises we hear when we are alone in the dark or the growl of an approaching animal. Our fear response is a survival mechanism that tells us to stay alert and avoid dangerous situations. But when fear grips us without any real threat, it can harm our emotional well-being and even deteriorate our health.
This is the case for people who have experienced severe or prolonged stressful situations, which can cause them to experience fear later in other moments or situations, even if they are not exposed to any risk. Experiencing this generalisation of fear is psychologically damaging and can lead to long-term mental health problems, such as post-traumatic stress disorder (PTSD).
The stress-induced mechanisms that cause our brains to produce feelings of fear in the absence of threats have largely been a mystery. Now, neurobiologists at the University of California, San Diego (UC San Diego) have identified the changes in brain biochemistry and mapped the neural circuitry that cause this experience of generalized fear. The results of their research have been published in the journal Science and offer new insights into how fear responses might be prevented.
In the paper, former UC San Diego assistant project scientist Hui-quan Li, now a senior scientist in Neurocrine Biosciences, Atkinson Family Distinguished Professor Nick Spitzer of the School of Biological Sciences, and colleagues describe research that led to the discovery of neurotransmitters – the chemical messengers that allow neurons in the brain to communicate with each other – at the root of widespread stress-induced fear.
How to avoid the appearance of generalized fear
By studying the brains of mice in an area known as the dorsal raphe (located in the brain stem), researchers found that acute stress induced a shift in chemical signals in neurons from the excitatory neurotransmitter “glutamate” to the inhibitory GABA, leading to generalized fear responses.
“Our results provide important insights into the mechanisms involved in fear generalization,” said Spitzer, a member of the Department of Neurobiology and the Kavli Institute for Brain and Mind at UC San Diego. “The benefit of understanding these processes at this level of molecular detail – what is happening and where it is happening – allows for intervention that is specific to the mechanism driving related disorders.”
Based on this new finding of a stress-induced shift in neurotransmitters, considered a form of brain plasticity, the researchers also examined the post-mortem brains of humans who had suffered from PTSD. A similar shift of neurotransmitters from glutamate to GABA was also confirmed in their brains.
“Now that we know the core mechanism by which stress-induced fear is produced and the circuits that implement this fear, interventions can be targeted and specific.”
The researchers then found a way to stop the production of generalized fear. Before the acute stress experience, they injected the dorsal blast of mice with an adeno-associated virus (AAV) to suppress the gene responsible for GABA synthesis. This method prevented the mice from acquiring generalized fear. Furthermore, when the mice were treated with the antidepressant fluoxetine (marketed as Prozac) immediately after a stressful event, transmitter switching and the subsequent appearance of generalized fear were prevented.
The researchers not only identified the location of the neurons that changed their transmitter, but also demonstrated the connections of these neurons with the central amygdala and lateral hypothalamus, brain regions previously linked to the generation of other fear responses. “Now that we know the core mechanism by which stress-induced fear occurs and the circuits that implement this fear, interventions can be targeted and specific,” Spitzer concludes.
