Chemical changes in the brain turn stress into fear

A team of neurobiologists has discovered how stress in disorders such as PTSD turns into fear in the brain and how this can be blocked

Our nervous system is programmed to feel fear. Whether it’s the scary noises we hear alone in the dark or the growl of a threatening animal approaching, our fear response is a survival mechanism that tells us to stay alert and avoid dangerous situations.

However, when fear arises in the absence of concrete threats, it can be detrimental to our well-being. Those who have experienced episodes of severe or life-threatening stress may later experience intense feelings of anxiety, even in situations where there is no real threat. Experiencing this generalized fear is psychologically damaging and can lead to long-term debilitating psychological disorders such as post-traumatic stress disorder (PTSD).

Fear in the brain

New research published in Science identifies the brain biochemistry and neural circuits that produce the experience of generalized fear. HERE ARE NEURONS SHOWN IN CYAN AND RETROGRADE TRACKS IN YELLOW AND MAGENTA. IMAGE: SPITZER LAB, UC SAN DIEGO

The stress-related mechanisms that cause our brains to generate feelings of fear in the absence of threats are largely a mystery. Now neurobiologists at the University of California, San Diego have identified changes in the brain’s biochemistry and mapped the neural circuits that cause this experience of general fear. Their research, published in the journal Science, provides new insights into how fear reactions could be prevented.

From excitement to inhibition

In their report, Hui-quan Li, former associate project scientist at UC San Diego (now senior scientist at Neurocrine Biosciences), Nick Spitzer, Atkinson Family Distinguished Professor in the School of Biological Sciences, and colleagues describe the research on which the discovery is based It is a series of neurotransmitters – the chemical messengers that allow neurons in the brain to communicate with each other – and is the cause of general anxiety caused by stress.

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By studying the brains of mice in an area known as the dorsal raphe (located in the brainstem), the researchers discovered that acute stress triggered a change in the chemical signals of neurons, switching from the excitatory neurotransmitters “glutamate” to the inhibitory ones “GABA,” which caused general fear responses.

“Our results provide important information about the mechanisms involved in fear generalization,” says Spitzer, a member of the Department of Neurobiology and the Kavli Institute for Brain and Mind at the University of California, San Diego. “The advantage of understanding these processes at this molecular level of detail – what happens and where it happens – enables targeted intervention in the mechanism that drives the associated disorders.”

Understanding Fear to Heal Post-Traumatic Stress

Building on this new finding of a stress-induced change in neurotransmitters, thought to be a form of brain plasticity, the researchers next examined the postmortem human brains of individuals who had suffered from PTSD (post-traumatic stress disorder). A similar switch from the neurotransmitter glutamate to GABA was also confirmed in their brains.

Next, the researchers found a way to stop the emergence of widespread fear. Before exposing them to acute stress, they injected the mice with an adeno-associated virus (AAV) to suppress the gene responsible for GABA synthesis. This method prevented the mice from developing generalized anxiety.

Furthermore, when mice were treated with the antidepressant fluoxetine (known as Prozac) immediately after a stressful event, channel switching and the subsequent onset of generalized anxiety were prevented.

The researchers not only identified the location of the neurons that switched their transmitter, but also showed the connections of these neurons to the central amygdala and lateral hypothalamus, brain regions previously linked to generating other fear responses.

“Now that we know the core mechanism by which stress-related anxiety arises and the circuits that implement it, interventions can be selective and specific,” says Spitzer.

REFERENCE

Generalized anxiety following acute stress is caused by a change in neuronal cotransmitter identity

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