Dopamine is Involved in Switching from Feelings of Fear to Safety

What's the science?

Moving on from negative experiences requires identifying when it is no longer appropriate to be fearful. Understanding the neurobiology of fear is important for disorders like post-traumatic stress disorder. Dopamine neurons originating in the brainstem (the ventral tegmental area) release dopamine in limbic (i.e. emotional) regions of the brain and are involved in signalling when outcomes are better than expected. Therefore, these neurons may be involved in transitioning from ‘fear responding’ to ‘safety’. This week in Nature Communications Luo and colleagues investigate how midbrain dopamine neurons are involved in extinguishing fear responses.

How did they do it?

Rats were exposed to a foot shock paired with an auditory stimulus. One day later, rats were exposed to the auditory stimulus (without foot shock) and underwent an ‘extinction learning’ session where the freezing (i.e. fear) response to the auditory stimulus is reduced or unlearned over time. Another day later, they were cued with the auditory stimulus again to see whether the fear response was completely gone. They used an optogenetic approach to silence the activity of midbrain dopamine neurons in these rats during the precise time period of extinction learning when the expected shock did not occur, to see whether midbrain dopamine was responsible for the extinction of fear memories. They then tested how extinction is occurring on a molecular level using optogenetics combined with immunohistochemistry.

What did they find?

Control mice demonstrated reduced freezing responses typical of fear extinction, while mice with silenced midbrain dopamine neuron firing showed a reduction in fear extinction (i.e. they still had freezing responses despite the extinction training). Since the phosphorylation of MAP kinase (MAPK) has been shown to mediate fear extinction, they tested to see whether levels of phosphorylated MAPK were lower in the rats who lacked fear extinction. They found, using immunohistochemistry, that MAPK levels were lower during the extinction training in mice whose dopamine neurons were inhibited. This suggests that dopamine neuron activity engages this molecular process during fear extinction. They then examined whether dopamine release has different effects on fear extinction learning at different release sites. They found that specifically inhibiting nerve terminals in the nucleus accumbens (a brain region involved in reward) reduced fear extinction, whereas inhibiting terminals in the ventromedial prefrontal cortex enhanced fear extinction (i.e. rats more effectively reduced their fear response). This suggests that nucleus accumbens dopamine mediates (i.e. promotes) fear extinction, while dopamine in the ventromedial prefrontal cortex opposes fear extinction. Using retrograde tracers, they found that the projections to the shell of the nucleus accumbens, rather than the core of the nucleus accumbens, mediated fear extinction.

What's the impact?

This is the first study to demonstrate that dopamine activity that occurs when an expected aversive outcome does not occur is involved in reducing fear responses to a fearful stimulus. We now know that midbrain dopamine neurons projecting to the nucleus accumbens play a critical role in overcoming fear responses when they are no longer appropriate (i.e. safe situations). Understanding the biology of fear extinction provides a better understanding of detrimental fear responses in anxiety disorders.

Luo et al., A dopaminergic switch for fear to safety transitions. Nature Communications (2018). Access the original scientific publication here.