New research from the University of California San Diego has uncovered how acute stress can rewire the Brain Mechanism, leading to generalized fear responses commonly seen in post-traumatic stress disorder (PTSD).
The study, published in Science on March 15, 2024, identifies specific biochemical changes in neurotransmitters that cause fear to persist even without actual threats. This discovery could pave the way for targeted PTSD treatments.
The Brain’s Fear Response and Its Link to PTSD
Fear is a fundamental survival mechanism, helping humans recognize and respond to danger. However, in individuals who have experienced extreme stress or trauma, this system can become dysregulated, leading to persistent and excessive fear in non-threatening situations. This fear generalization can have debilitating effects on mental health, often contributing to conditions like PTSD. Brain Mechanism
Until now, scientists have struggled to understand the exact mechanisms that cause this misfiring of fear responses. The new study, led by former UC San Diego researcher Hui-quan Li and Atkinson Family Distinguished Professor Nick Spitzer, reveals how acute stress alters neurotransmitter signaling in a key part of the brain, triggering long-lasting fear responses.
How Stress Rewires the Brain’s Fear Circuitry
The researchers focused on the dorsal raphe, a region in the brainstem that plays a crucial role in regulating fear and anxiety. Studying mouse models, they discovered that acute stress triggers a neurotransmitter switch—neurons that typically release the excitatory neurotransmitter glutamate instead of producing the inhibitory neurotransmitter GABA.
This glutamate-to-GABA switch disrupted standard fear processing, leading to generalized fear responses even in safe environments.
The researchers then examined the postmortem human brains of individuals with PTSD and found the same neurotransmitter switch, confirming that this process is relevant to human fear disorders.
“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. “Understanding these processes at a molecular level allows for interventions that directly target the mechanism driving these disorders.”
Blocking the Fear Response: A Potential Breakthrough for PTSD Treatment and Brain Mechanism
Beyond identifying how stress-induced fear happens, the researchers successfully prevented the process in mice.
- Genetic Intervention: By using an adeno-associated virus (AAV) to suppress the gene responsible for GABA synthesis, they stopped the neurotransmitter switch from occurring—preventing the development of generalized fear.
- Medication Intervention: Treating mice immediately after a stressful event with the antidepressant fluoxetine (Prozac) also blocked the neurotransmitter switch and stopped the onset of persistent fear responses.
Further brain mapping confirmed that the affected neurons connect to the central amygdala and lateral hypothalamus, regions previously linked to fear processing.
Reference: Hui-quan Li, Wuji Jiang, Li Ling, Marta Pratelli, Cong Chen, Vaidehi Gupta, Swetha K. Godavarthi, Nicholas C. Spitzer. Generalized fear after acute stress is caused by change in neuronal cotransmitter identity. Science, 2024.
