A dopaminergic switch for fear to safety transitions

Ray Luo,Luca Aquili,Adam Weitemier,Joshua P Johansen,Akira Uematsu,Thomas J Mchugh,Jenny Koivumaa

doi:10.1038/s41467-018-04784-7

Abstract

Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate so that they can be extinguished. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signaling when a better-than-expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signaling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. In contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioral roles for different dopamine neuron projections in fear extinction learning.

Highlights

Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate so that they can be extinguished
To do this we expressed enhanced yellow fluorescent protein alone or the inhibitory Halorhodopsin fused to eYFP in ventral tegmental area (VTA)-dopamine cells of tyrosine hydroxylase-cre recombinase (TH-Cre) rats[24] by injecting a Cre-dependent adeno-associated virus (AAV) into the VTA (Fig. 1a, b and Supplementary Fig. 1)
This demonstrates distinct VTA-dopamine cell populations projecting to core and medial shell (mShell) and reveals a novel function for the mShell projecting cells in modulating the persistence of extinction memories. These findings show that activation of VTA-dopamine neurons during the expected shock omission time period is necessary for normal extinction learning and the upregulation of extinctionrelated plasticity markers in the ventromedial prefrontal cortex (vmPFC) and amygdala

Summary

Introduction

Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate so that they can be extinguished. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signaling when a better-than-expected outcome has occurred This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signaling events in extinction learning circuits. A separate projection of the VTA-dopamine system to the vmPFC opposes extinction learning Together, these results demonstrate that the VTA-dopamine system is necessary for detecting when aversive responses should be reduced and reveal that distinct populations of dopamine neurons make unique and specific contributions to this process

Methods

Results

Conclusion