The Role of Dopamine Neurons During Mouse Fear Conditioning and Extinction

Abstract

Dopamine is well known for its role in reward learning, however, its role in fear learning is unclear. For example, dopamine neurons encode a reward prediction error that contributes to creating and extinguishing rewarding associations -- is this also true for aversive associations? To address this question, I used fiber photometry and optogenetics to record and manipulate bulk dopamine neuron activity in different brain regions to dissect how they instruct fear conditioning and extinction. I also introduce an automated pipeline using deep learning to label mouse freezing (a fear-induced behavior), to eliminate the need for human labeling.

Consistent with findings that dopamine neurons can display spatially organized signals across the ventral tegmental area (VTA), I found subpopulations that encoded distinct aspects of fear learning. In particular, during fear extinction, dopamine neuron activity in medial VTA closely reflected reward prediction error while activity in lateral VTA reflected salience, where salience is defined as the absolute value of reward prediction error. The magnitude of both signals correlated with mouse freezing behavior across trials and explained individual variability across mice. Inhibiting dopamine neurons in either region slowed fear extinction, with the relevant time period for inhibition differing across regions. These findings support a burgeoning line of research dissecting specific roles of dopamine neuron subpopulations, and illuminates a causal role for salience in learning.

Extending on the idea that dopamine neurons are topographically organized by their downstream projections, dopamine axon signals in the striatum also showed spatial organization during fear learning. Dopamine axons in the nucleus accumbens core and dorsal-medial striatum shared similar attributes with cell bodies in medial VTA, while axons in dorsal-lateral striatum did not.

Together, the data show spatially defined roles for dopamine neurons during fear conditioning and extinction. Understanding how different dopaminergic pathways instruct fear extinction could guide targeted pharmacotherapies for fear-related disorders such as post-traumatic stress disorder.