In every living being through history, stress from a perceived threat has automatically and immediately triggered an avalanche of reactions.
‘Fight or flight’ is an example of the choices these life-forms have confronted. Every bodily function that isn’t essential for survival is moved to the sidelines as the being prepares to respond. All available resources are diverted to extricating oneself from the threatening situation.
In this sense, stress has been good for the body and for the species.
Fear response
But it comes at a cost. Stress can also cause long term changes in defensive responses. For starters, it can exaggerate how you respond to a threat. If someone were attacked in a dark street, they could become afraid of any dark environment, like in movie theatres. This is called stress-enhanced fear learning.
Stress can also induce a fear of objects and situations unrelated to the original threat. This is called a stress-enhanced fear response (SEFR).
SEFR has been connected to anxiety disorders, phobias, and post-traumatic stress disorder (PTSD). The question of why this connection exists recently prompted scientists at the University of Texas, Austin, and the University of California, Los Angeles, to closely investigate it in a mouse model.
They found that they were able to induce SEFR in the mice when they were confronted with new cues unrelated to a stressor. This then prompted the team to design careful experiments to identify the precise brain regions and mechanisms driving such behaviour, paving the way for better clinical treatments for conditions like PTSD.
Experimental setup
The team confined lab mice in a conditioning chamber, an aluminium box with a clear door and about a foot long on each side. The control group animals were undisturbed while the stress group was administered a mild electrical footshock (1 mA) at random intervals.
Then the team gave the mice context exposure: the two groups were placed in the same chamber but received no footshock this time. For mice that had received the shocks earlier in a similar chamber, their surroundings sufficed to trigger a freeze response, i.e. they became completely immobile yet hyper-alert.
Freezing isn’t a conscious choice and happens automatically.
Out in the wild, mice are prey animals, so their self-preservation repertoire includes freezing, fleeing, and simply hoping to avoid detection (e.g. from a predator flying overhead). In the conditioning chamber, the confinement only induced the freeze response.
Next, the team placed these mice in a different chamber, i.e. exposed them to a new context, where they received new stimuli in the form of brief sounds. Even here, the mice displayed a heightened freeze response — an example of unlearned fear and thus of SEFR at work.
Curiously, the stress group mice froze only after they heard the audio tones, not otherwise. It was a sign that the stress mice hadn’t generalised the freeze response.
Follow the light
How does the brain develop unlearned fear?
The scientists peered into the brains of the stress group mice looking for a particular protein called c-fos. This protein is the “time to get to work” signal for brain cells. They found a part of a brain region called the paraventricular thalamus (PVT) expressing high amounts of c-fos after the audiotone test, but only in mice that received both the footshock on day 1 and the audio tone test later.
If the animals hadn’t faced the footshocks on day 1 or had received the shocks but no audio tone test after, the amounts of c-fos didn’t change. In other words, increases in c-fos in the PVT were specific to the unlearned fear response.
The PVT is named thus because it’s a part of the thalamus and is localised around (“para”) the third ventricle, one of the cavities inside the brain. The thalamus is a somewhat egg-shaped structure located roughly at the middle of the brain. All information coming into the brain first comes here and is then relayed to other regions for interpretation and response.
The research team suspected that the unlearned fear response stemmed from the PVT being activated, and sought a way to confirm this independently.
When the cells in any brain region prepare to act, they use calcium ions to signal to their neighbours to get ready. So the team injected a calcium-sensing protein genetically modified to light up when it detected calcium. Their observations confirmed that neurons in a part of the PVT were getting activated when the unlearned fear response was on show.
They also showed that when the activity in these neurons was blocked, the stress group mice didn’t develop the freezing response when exposed to the audio tones.
Remarkably, however, this blocking action didn’t change the stress-enhanced fear learning in these mice, proving that the activation of PVT neurons was specific to SEFR.
When more is too much
The experiments by the international team showed that unlearned fear is caused by increased activity in PVT neurons. This is why the team’s study is fascinating: the findings highlight that PVT fine-tunes different defensive responses differently.
For example, learned fear behaviour is adaptive, allowing us to respond appropriately to environmental cues. But stressful or traumatic experiences can ratchet this response up manifold in response to both learned, like in the dark movie theatre, and unlearned fears, as with PTSD.
In fact, unlearned fear responses have been particularly difficult to treat because scientists didn’t fully understand their causes. The new finding, of specific activity in the PVT neurons, may now lead them to new avenues to clinically treat symptoms.
Dr. Reeteka Sud is a neuroscientist by training and senior scientist at the Center for Brain and Mind, Department of Psychiatry, NIMHANS, Bengaluru.
Published – November 11, 2025 04:24 pm IST
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