Mice are experts at learning fears, and they’re experts at unlearning them, too. But what allows these animals to push past their terror when something that was a threat isn’t a threat anymore? According to a new study in the Proceedings of the National Academy of Science (PNAS), a dopamine circuit in the brain sends out the signals that initiate fear extinction in mice, enabling these animals to overcome their trepidations.
“Dopamine is essential to initiate fear extinction,” said Michele Pignatelli di Spinazzola, a study author and a neuroscientist at MIT, according to a press release.
Indeed, the new study points to dopamine as an important mechanism for managing fear in mice as well as in humans, as dopamine dysfunctions could contribute to human conditions like anxiety and post-traumatic stress disorder.
Read More: How the Brain Recognizes and Rationalizes Fear
Learning and Unlearning Fear
Back in 2020, MIT researchers figured out that a mouse’s ability to learn and unlearn a fear traces to the neurons in its amygdala, an area of the brain that regulates the experience of emotions, the encoding of memories, and even the activation of the fight-or-flight response.
Bringing mice to an enclosure and zapping their feet with tiny electric shocks, then bringing the mice back to the enclosure without zapping their feet, the researchers revealed which neurons are activated in the anterior basolateral amygdala (aBLA) when a mouse learns and unlearns a fear. When the former occurs, the neurons that express the gene Rspo2 are activated, encoding a fear memory. But when the latter happens, the neurons that express the gene Ppp1r1b are activated instead, creating a fear extinction memory that overrides the fear itself.
Returning to this research in the PNAS study, MIT researchers set out to find the mechanism that tells the Ppp1r1b neurons, which are also involved in the experience of reward, to encode for fear extinction.
“Our study uncovers a precise mechanism by which dopamine helps the brain unlearn fear,” said Xiangyu Zhang, a study author and a former neuroscientist at MIT, according to a press release. “We found that dopamine activates specific amygdala neurons tied to reward, which in turn drive fear extinction. We now see that unlearning fear isn’t just about suppressing it — it’s a positive learning process powered by the brain’s reward machinery.”
Read More: What is Anxiety and How Can Worries Overpower Us?
Follow the Dopamine
Looking to the ventral tegmental area (VTA), a region of the brain associated with surprises, learning, and reward, the team’s first step was to confirm that a dopamine circuit connects the VTA and the amygdala. Tracking the neural connectivity between the two regions, the team demonstrated that the neurons in the VTA connect to the Rspo2 and Ppp1r1b neurons, with the Ppp1r1b neurons receiving the bulk of the connections. Then, testing the dopamine activity between the two regions, the team determined that the Rspo2 and Ppp1r1b neurons in the amygdala have dopamine receptors (and thus the ability to receive dopamine from the VTA), with the Ppp1r1b neurons again having more receptors.
With this circuitry confirmed, the researchers tracked the dopamine activity in mice’s brains as they learned and unlearned a fear. Establishing that the amygdala neurons react to dopamine as fears are encoded and extinguished, the researchers discovered that Rspo2 neurons are more responsive during fear encoding, while Ppp1r1b neurons have stronger responses to dopamine during fear extinction.
The team’s final step was to verify that the dopamine circuit between the VTA and the amygdala causes fears to be learned and unlearned. Activating and deactivating the stream of dopamine from the VTA to the Rspo2 and the Ppp1r1b neurons, the researchers revealed that they could accelerate and decelerate both fear encoding and extinction. And tinkering with the dopamine receptors in the amygdala, they also realized that a disruption of receptors in the Rspo2 neurons disturbed fear encoding while interference with receptors on the Ppp1r1b neurons hindered fear extinction.
According to the researchers, this work isolates the circuit that initiates fear extinction, not the circuit that enacts it, which would be a broader network of brain regions. Yet this dopamine circuit between the VTA and the amygdala is still important, with potentially vital implications for human health.
“Fear learning and fear extinction provide a strong framework to study generalized anxiety and PTSD,” Pignatelli di Spinazzola said in the release.
With these human conditions, fears are learned, though they aren’t always efficiently extinguished.
“This opens up new avenues for understanding and potentially treating fear-related disorders,” Zhang added in the release.
Read More: If Anxiety Is In My Brain, Why Is My Heart Pounding? A Psychiatrist Explains The Neuroscience And Physiology Of Fear
Article Sources
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Sam Walters is a journalist covering archaeology, paleontology, ecology, and evolution for Discover, along with an assortment of other topics. Before joining the Discover team as an assistant editor in 2022, Sam studied journalism at Northwestern University in Evanston, Illinois.
