How Dopamine Helps The Brain Forget Fear

Our brains can “unlearn” old fears when they realize we are safe, a process called fear extinction. A study in mice showed that a type of chemical in the brain, dopamine, helps activate parts of the memory responsible for this unlearning. By stimulating these areas precisely, scientists were able to speed up the overcoming of fear, which could pave the way for new treatments for disorders such as PTSD.

Our brains need to be able to forget or control old fears when they are no longer necessary. This process is called fear extinction and is essential for our mental health. For example, if you were bitten by a dog as a child, your brain learned to be afraid of dogs. But over time, by living with harmless dogs, this fear can diminish.

This “unlearning” is what we call fear extinction. This mechanism helps to balance our emotions and prevent negative memories from dominating our reactions. When it fails, it can contribute to illnesses such as post-traumatic stress disorder (PTSD).

Fear extinction depends on a part of the brain called the basolateral amygdala (BLA), which is involved in the formation of emotional memories.

In this region, there are two main types of nerve cells: one that stores fear (called Rspo2+ neurons, located in the front part of the basolateral amygdala), and another that helps to erase this fear and is related to positive feelings (called Ppp1r1b+ neurons, located in the back part of the basolateral amygdala).

During fear extinction, these Ppp1r1b+ cells create a new positive memory that reduces the fear stored by the Rspo2+ cells.

But how does the brain decide when it’s time to “turn off” fear? It does so when an expected bad stimulus, such as a shock, doesn’t happen. This absence of danger is perceived as something good, and this relief generates a “learning signal” in the brain.

This signal appears to come from another area called the ventral tegmental area (VTA), which produces dopamine, a chemical important for learning and motivation. Scientists believe that during fear extinction, dopamine released by the ventral tegmental area may help the brain understand that it is safe and thus form a new fear-free memory.

To test this idea, scientists at the Massachusetts Institute of Technology, USA, used rats and a series of modern techniques.

First, they traced the connections between the ventral tegmental area and the basolateral amygdala to see which types of neurons were communicating. They then used a method called fiber photometry, which allows them to observe brain activity in real time, measuring dopamine levels as the rats underwent fear-unlearning sessions.

They then used a technique called optogenetics, which works like a light “remote control” to turn specific brain cells on or off, activating or inhibiting the release of dopamine in the desired areas.

(A) A drawing showing that scientists injected a virus (AAV) with a glowing protein (EYFP) into the ventral tegmental area of ​​mice. This virus enters only the neurons that release dopamine (in mice with a gene called DAT-IRES-Cre). This allows them to trace the pathways of dopamine neurons that lead to the amygdala.

(B) Actual brain images. On the left, we see the ventral tegmental area with green (dopamine) neurons. On the right, we see the amygdala, with green fibers (which came from the ventral tegmental area) spreading into two areas: aBLA (anterior, marked with red cells called Rspo2+), and pBLA (posterior, with red cells called Ppp1r1b+, which help extinguish fear). These images show that neurons in the ventral tegmental area project to these two areas differently.

(C) A graph showing the average amount of green signal (fluorescence intensity) in three regions of the amygdala, suggesting that more dopamine is arriving there.

(D-F) These panels show another approach: this time using a modified rabies virus that “returns” through the nerve connections. This allows us to find out where the signals that reach specific neurons in the amygdala are coming from. (D) shows a schematic of injection of the virus into the aBLA of mice with Rspo2+ (fear-related) neurons. (E) shows the actual images, revealing that many VTA neurons send signals to the Rspo2+ neurons in the aBLA. (F) shows the same technique applied to the pBLA in mice with Ppp1r1b+ (fear-extinction) neurons.

(G) shows that another population of the ventral tegmental area sends signals to these Ppp1r1b+ neurons.

(H) This graph shows the location of the neurons in the ventral tegmental area that connect to the two areas of the amygdala (Rspo2+ and Ppp1r1b+). The lines show that the neurons connected to the aBLA (fear) and the pBLA (fear extinction) come from different parts of the ventral tegmental area. In other words, the brain sends dopamine to these two areas in very different ways, depending on the type of information (fear or safety).

The results showed that when dopamine reached the fear-extinction cells (Ppp1r1b+), the mice learned more quickly that they were safe. When the scientists artificially increased this dopamine activity, the animals overcame their fear more quickly.

On the other hand, when dopamine was directed to the fear-extinction cells (Rspo2+), extinction was more difficult and the fear persisted. This proves that dopamine can influence learning in a bidirectional way: it can either help to erase fear or reinforce it, depending on where in the brain it acts.

During fear learning (such as when an animal receives a small shock after hearing a sound), two areas of the brain called Rspo2+ and Ppp1r1b+ in the basolateral amygdala (BLA) come into play. Both receive a chemical signal called dopamine (DA), released by another part of the brain called the ventral tegmental area (VTA). However, at this moment, dopamine activates more strongly the Rspo2+ neurons, which are linked to the feeling of fear. These neurons then inhibit the Ppp1r1b+ neurons, which are linked to more positive responses, such as the feeling of safety. This causes the animal to freeze, that is, become paralyzed by fear. On the other hand, when the animal goes through a process of "unlearning fear", that is, realizes that the sound is no longer followed by a shock, the situation changes. Now, dopamine is released mainly in the Ppp1r1b+ neurons, which are linked to the feeling of safety. They then inhibit Rspo2+, causing the animal to stop freezing. This shows how the brain uses dopamine to help switch the fear response to a safety response, depending on what is happening around it.

In short, this study shows that there is a specific “chemical pathway” in the brain, involving dopamine and well-defined areas of the amygdala, that helps us understand when it is safe to let go of fear.

This type of discovery is essential for creating new treatments for disorders like PTSD, which involve traumatic memories that are difficult to erase. If we can control these circuits precisely, we can teach the brain to unlearn fear more effectively.

READ MORE:

Dopamine induces fear extinction by activating the reward-responding amygdala neurons

Xiangyu Zhang, Katelyn Flick, Marianna Rizzo, and Susumu Tonegawa 

PNAS. April 28, 2025 122 (18) e2501331122

https://doi.org/10.1073/pnas.250133112

Abstract:

The extinction of conditioned fear responses is crucial for adaptive behavior, and its impairment is a hallmark of anxiety disorders such as posttraumatic stress disorder. Fear extinction takes place when animals form a new memory that suppresses the original fear memory. In the case of context-dependent fear memory, the new memory is formed within the reward-responding posterior subset of basolateral amygdala (BLA) that is genetically marked by Ppp1r1b+ neurons. These memory engram cells suppress the activity of the original fear-responding Rspo2+ engram cells present in the anterior BLA, hence fear extinction. However, the neurological nature of the teaching signal that instructs the formation of fear extinction memory in the Ppp1r1b+ neurons is unknown. Here, we demonstrate that ventral tegmental area (VTA) dopaminergic signaling drives fear extinction in distinct BLA neuronal populations. We show that BLA fear and extinction neuronal populations receive topographically divergent inputs from VTA dopaminergic neurons via differentially expressed dopamine receptors. Fiber photometry recordings of dopaminergic activity in the BLA reveal that dopamine (DA) activity is time-locked to freezing cessation in BLA fear extinction neurons, but not BLA fear neurons. Furthermore, this dopaminergic activity in BLA fear extinction neurons correlates with extinction learning. Finally, using projection-specific optogenetic manipulation, we find that activation of the VTA DA projections to BLA reward and fear neurons accelerated or impaired fear extinction, respectively. Together, this work demonstrates that dopaminergic activity bidirectionally controls fear extinction by distinct patterns of activity at BLA fear and extinction neurons.