Author response: Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes

Salinas-Hernández, Ximena I; Vogel, Pascal; Betz, Sebastian; Kalisch, Raffaël; Sigurdsson, Torfi; Duvarci, Sevil

doi:10.7554/elife.38818.024

Cited by 9 publications

(11 citation statements)

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“…We further show that signals in nucleus accumbens at the time-point of US omission were functionally coupled with activation in the amygdala and the SN/VTA, which were enhanced by administration of the dopaminergic precursor L-DOPA. This finding mirrors findings in animals implying neurons in the VTA, as well as projections from the VTA to the nucleus accumbens, in the encoding of the omission of an expected US [11,13]. Furthermore, our results would align with studies in animals that provided evidence for amygdala to nucleus accumbens projections that underlie extinction of threat responses [9].…”

Section: Discussionsupporting

confidence: 88%

“…However, it is only incompletely understood in humans which neural system detects the omission of the expected aversive outcome and, hence, initiates a shift from threat to safety. Studies in drosophila [5] and rodents [6][7][8][9][10][11][12]12] revealed that the omission of an expected aversive outcomes depends on signals in the dopaminergic system. In rodents, this involved dopaminergic neurons in the ventral tegmental area (VTA), the nucleus accumbens and the medial prefrontal cortex, as well as projections between the VTA and nucleus accumbens [6,9,13,14].…”

Section: Introductionmentioning

confidence: 99%

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L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans

Esser

Korn

Ganzer

et al. 2020

Preprint

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Learning to be safe is central to adjust behaviour when threats are no longer present. Detecting the absence of an expected threat is key for threat extinction learning and behavioural treatment of anxiety related disorders. One possible mechanism underlying extinction learning is a dopaminergic mismatch signal that encodes absent but expected threats. We show that a dopamine-related pathway underlies extinction learning in humans. Dopaminergic enhancement (L-DOPA/Placebo) reduced retention of psychophysiological threat responses, which was mediated by activity in the ventromedial prefrontalcortex during extinction learning. L-DOPA administration enhanced signals at the timepoint of the omitted, but expected threat within the nucleus accumbens, which were functionally coupled with the ventral tegmental area and amygdala. Computational modelling of threat expectancies further revealed prediction-error encoding in nucleus accumbens that was modulated by dopaminergic enhancement. Our results provide a mechanism to augment extinction learning by enhancement of dopaminergic neurotransmission that underlies encoding of absent threats.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans

Esser

Korn

Ganzer

et al. 2020

Preprint

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“…Accumulating evidence suggests that dopamine reinforces fear extinction learning by signaling the omission of expected aversive US in both animals and humans (de Jong et al, 2019;Kalisch et al, 2019;Matsumoto and Hikosaka, 2009;Raczka et al, 2011;Luo et al, 2018;Salinas-Herná ndez et al, 2018). In the mesolimbic dopaminergic system, the amygdala receives dopaminergic input from the ventral tegmental area (VTA) and substantia nigra (SNc) in the midbrain (Brinley-Reed and McDonald, 1999;Pezze and Feldon, 2004).…”

Section: Intrinsic Reinforcement Signals During Fear Extinctionmentioning

confidence: 99%

Amygdala Reward Neurons Form and Store Fear Extinction Memory

Zhang

Kim

Tonegawa

2020

Neuron

177

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“…Moreover, impaired fear extinction was suggested as a relevant endophenotype for anxiety disorders and PTSD (Singewald and Holmes, 2019). Recently, it has been proposed that during extinction learning midbrain dopaminergic neurons encode a quasi-appetitive reward prediction error, signaling the omission of the aversive unconditioned stimulus as a 'better-than-expected' outcome (Luo et al, 2018;Salinas-Hernandez et al, 2018;Cai et al, 2020). Besides this temporally restricted role in extinction acquisition, dopamine was also suggested to play a key role in the consolidation phase in a human fMRI study (Gerlicher et al, 2018).…”

Section: Interaction Of Ghrelin With Neurotransmitter Systems As a Gamentioning

confidence: 99%

The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders

Fritz

Singewald

Bundel

2020

Front. Synaptic Neurosci.

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Ghrelin is a peptide hormone released by specialized X/A cells in the stomach and activated by acylation. Following its secretion, it binds to ghrelin receptors in the periphery to regulate energy balance, but it also acts on the central nervous system where it induces a potent orexigenic effect. Several types of stressors have been shown to stimulate ghrelin release in rodents, including nutritional stressors like food deprivation, but also physical and psychological stressors such as foot shocks, social defeat, forced immobilization or chronic unpredictable mild stress. The mechanism through which these stressors drive ghrelin release from the stomach lining remains unknown and, to date, the resulting consequences of ghrelin release for stress coping remain poorly understood. Indeed, ghrelin has been proposed to act as a stress hormone that reduces fear, anxiety-and depression-like behaviors in rodents but some studies suggest that ghrelin may-in contrast-promote such behaviors. In this review, we aim to provide a comprehensive overview of the literature on the role of the ghrelin system in stress coping. We discuss whether ghrelin release is more than a byproduct of disrupted energy homeostasis following stress exposure. Furthermore, we explore the notion that ghrelin receptor signaling in the brain may have effects independent of circulating ghrelin and in what way this might influence stress coping in rodents. Finally, we examine how the ghrelin system could be utilized as a therapeutic avenue in stressrelated psychiatric disorders (with a focus on anxiety-and trauma-related disorders), for example to develop novel biomarkers for a better diagnosis or new interventions to tackle relapse or treatment resistance in patients.

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Author response: Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes

Cited by 9 publications

References 0 publications

L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans

L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans

Amygdala Reward Neurons Form and Store Fear Extinction Memory

The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders

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