Distinct signals in medial and lateral VTA dopamine neurons modulate fear extinction at different times.

Lili X Cai,Cameron L Hayes,Julia M Cox,Weston T Fleming,Sebastian Holt,Gregory W Gundersen,Katherine Pizano,Ilana B Witten

doi:10.7554/elife.54936

Abstract

Dopamine (DA) neurons are to encode reward prediction error (RPE), in addition to other signals, such as salience. While RPE is known to support learning, the role of salience in learning remains less clear. To address this, we recorded and manipulated VTA DA neurons in mice during fear extinction. We applied deep learning to classify mouse freezing behavior, eliminating the need for human scoring. Our fiber photometry recordings showed DA neurons in medial and lateral VTA have distinct activity profiles during fear extinction: medial VTA activity more closely reflected RPE, while lateral VTA activity more closely reflected a salience-like signal. Optogenetic inhibition of DA neurons in either region slowed fear extinction, with the relevant time period for inhibition differing across regions. Our results indicate salience-like signals can have similar downstream consequences to RPE-like signals, although with different temporal dependencies.

Highlights

A critical function of VTA DA neurons is to signal reward prediction error (RPE), or the difference between experienced and expected reward (Schultz et al, 1997; Cohen et al, 2012)
Each classifier achieved optimal training within 50 training epochs (Figure 1—figure supplement 1B–E) and yielded 92–96% accuracy, 5–10% false positive rate (FPR) and 4–6% false negative rate (FNR) (Figure 1D). This was comparable to the relative performance between two humans: given one person’s scoring held as ground truth, the other person scored with 95% accuracy, 11.5% FPR and 0.3% FNR (Figure 1—figure supplement 1F)
We found that dopamine axons in the nucleus accumbens and dorsal medial striatum (DMS) both showed RPE during fear extinction, similar to dopamine cell bodies in medial VTA (Figure 3—figure supplement 5)

Summary

Introduction

A critical function of VTA DA neurons is to signal reward prediction error (RPE), or the difference between experienced and expected reward (Schultz et al, 1997; Cohen et al, 2012). VTA DA neurons were shown to represent RPE-like signals during fear extinction, in that they display elevated activity when the shock is omitted at the offset of the cue, signaling better-than-expected outcome (Salinas-Hernandez et al, 2018; Badrinarayan et al, 2012; Jo et al, 2018). Manipulation of this activity altered the rate of extinction, suggesting that an RPE-like signal in DA neurons drives reinforcement learning for aversive associations as well as rewarding associations (Salinas-Hernandez et al, 2018; Luo et al, 2018)

Methods

Results

Conclusion