CAMBRIDGE, Mass. — When danger passes, the brain needs a way to signal that it’s safe again. A new study by MIT neuroscientists reveals that the brain releases dopamine along a specific neural pathway to help extinguish fear. The findings, based on experiments in mice, highlight a crucial mechanism for mental health, with implications for anxiety disorders and post-traumatic stress disorder (PTSD).
“Dopamine is essential to initiate fear extinction,” said Michele Pignatelli di Spinazzola, co-author of the study conducted in the lab of Susumu Tonegawa, Picower Professor of Biology and Neuroscience at MIT’s RIKEN-MIT Laboratory for Neural Circuit Genetics.
The research, published in the Proceedings of the National Academy of Sciences, builds on Tonegawa’s previous work. In 2020, his team demonstrated that the brain’s amygdala encodes both fear and the unlearning of fear through competing groups of neurons. When mice associated a location with a mild foot shock, neurons expressing the Rspo2 gene in the anterior basolateral amygdala (aBLA) stored the fear memory. When the mice later learned that the location was safe, a different population—Ppp1r1b-expressing neurons in the posterior basolateral amygdala (pBLA)—encoded the extinction of that fear. These same pBLA neurons also signal reward, suggesting why relief feels so rewarding when perceived danger subsides.
In the new study, researchers led by Xiangyu Zhang and Katelyn Flick sought to uncover what triggers these memory-encoding neurons. Their experiments identified dopamine as the key, delivered to the amygdala by distinct groups of neurons in the ventral tegmental area (VTA).
“Our study uncovers a precise mechanism by which dopamine helps the brain unlearn fear,” said Zhang, now a Senior Associate at healthcare investment firm Orbimed. “We found that unlearning fear is not just about suppressing it — it’s a positive learning process driven by the brain’s reward system.”
Mapping the Fear Extinction Circuit
The researchers first confirmed that neurons in the VTA project to the amygdala. Using circuit-tracing methods, they found that Rspo2 neurons received dopaminergic input from the anterior VTA, while Ppp1r1b neurons were connected to the center and posterior sections of the VTA. Notably, connections were denser to the Ppp1r1b neurons.
Further analysis showed that both types of neurons express D1 dopamine receptors, but Ppp1r1b neurons had a higher density, aligning with their greater dopaminergic input.
To understand dopamine’s role during fear learning and extinction, the team tracked dopamine activity in the amygdala over a three-day behavioral experiment. On the first day, mice received mild foot shocks in a specific enclosure, leading to fear. On the second day, they returned to the same space but experienced no shocks. Initially, the mice froze in fear but gradually relaxed. On the third day, they were tested again to assess fear extinction.
Dopamine activity patterns matched the mice’s behavior. During initial fear learning, Rspo2 neurons showed greater dopamine responses. During fear extinction, Ppp1r1b neurons displayed stronger dopamine signals. Mice that extinguished fear more effectively had the most pronounced dopamine activity in Ppp1r1b neurons.
Demonstrating Cause and Effect
The researchers then tested whether dopamine activity was not just correlated with fear extinction but caused it. Using optogenetics—a technique that uses light to control neurons—they manipulated dopaminergic signals to the amygdala.
When they suppressed VTA dopamine input to the pBLA, mice had difficulty extinguishing fear. Conversely, stimulating these inputs accelerated fear extinction. Surprisingly, activating dopamine inputs into the aBLA reinstated fear even without new shocks, impairing extinction.
Further experiments focused on dopamine receptors in amygdala neurons. Increasing D1 receptor expression in Ppp1r1b neurons enhanced extinction, while reducing receptors impaired it. In Rspo2 neurons, knocking down D1 receptors decreased fear responses.
“We demonstrated that fear extinction requires VTA dopaminergic activity in pBLA Ppp1r1b neurons, using both optogenetic inhibition and receptor knockdown techniques,” the authors wrote.
Implications for Mental Health
The team emphasized that while they identified a critical circuit, fear extinction is a brainwide process. Nevertheless, targeting the VTA-amygdala dopamine pathway may offer promising strategies for treating anxiety and PTSD.
“Fear learning and fear extinction provide a strong framework for studying generalized anxiety and PTSD,” said Pignatelli di Spinazzola. “Our study suggests multiple potential therapeutic targets, including the pBLA and dopaminergic modulation.”
Marianna Rizzo also contributed as a co-author. The research received support from the RIKEN Center for Brain Science, the Howard Hughes Medical Institute, the Freedom Together Foundation, and MIT’s Picower Institute for Learning and Memory.
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