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

Authors:
  • EU Horizon2020 project DynaMORE (Dynamic MOdelling of REsilience)

Abstract

Extinction of fear responses is critical for adaptive behavior and deficits in this form of safety learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate extinction learning are largely unknown. Here we show, using single-unit electrophysiology and cell-type specific fiber photometry, that dopamine neurons in the ventral tegmental area (VTA) are activated by the omission of the aversive unconditioned stimulus (US) during fear extinction. This dopamine signal occurred specifically during the beginning of extinction when the US omission is unexpected, and correlated strongly with extinction learning. Furthermore, temporally-specific optogenetic inhibition or excitation of dopamine neurons at the time of the US omission revealed that this dopamine signal is both necessary for, and sufficient to accelerate, normal fear extinction learning. These results identify a prediction error-like neuronal signal that is necessary to initiate fear extinction and reveal a crucial role of DA neurons in this form of safety learning.
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... In the context of reward, it is well-established that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra (SN) of the midbrain increase their firing rate to unexpected rewards (positive PE), suppress their firing for unexpected reward omissions (negative PE) and show no change in firing in response to completely predicted rewards, in line with a formalized PE (Schultz, 2016;Watabe-Uchida et al., 2017). Likewise, in fear extinction, dopaminergic neurons in the VTA phasically increase their firing rates to early (unexpected), but not late (expected) US omissions (Luo et al., 2018;Salinas-Hernández et al., 2018;Cai et al., 2020;de Jong et al., 2019;Badrinarayan et al., 2012), which consequently triggers downstream dopamine release in the nucleus accumbens (NAc) shell (Luo et al., 2018;de Jong et al., 2019;Badrinarayan et al., 2012). Furthermore, optogenetically blocking (or enhancing) the firing rate of these dopaminergic VTA neurons during US omissions impairs (or facilitates) subsequent fear extinction learning (Luo et al., 2018;Salinas-Hernández et al., 2018;Cai et al., 2020). ...
... Likewise, in fear extinction, dopaminergic neurons in the VTA phasically increase their firing rates to early (unexpected), but not late (expected) US omissions (Luo et al., 2018;Salinas-Hernández et al., 2018;Cai et al., 2020;de Jong et al., 2019;Badrinarayan et al., 2012), which consequently triggers downstream dopamine release in the nucleus accumbens (NAc) shell (Luo et al., 2018;de Jong et al., 2019;Badrinarayan et al., 2012). Furthermore, optogenetically blocking (or enhancing) the firing rate of these dopaminergic VTA neurons during US omissions impairs (or facilitates) subsequent fear extinction learning (Luo et al., 2018;Salinas-Hernández et al., 2018;Cai et al., 2020). Notably, such dopaminergic VTA/NAc responses to threat omissions have also been observed in other experimental tasks, such as conditioned inhibition Yau and McNally, 2018 and avoidance (Oleson et al., 2012;Wenzel et al., 2018), confirming that these neural activations match a more general threat omission PE-signal. ...
... First, it remains unclear whether these activations reflect the activity of dopamine cells in this region. The dopamine basis of the reward PE is well established (Schultz, 2016;Watabe-Uchida et al., 2017), and similar VTA dopaminergic responses to threat omissions have been found during fear extinction in rodents (Luo et al., 2018;Salinas-Hernández et al., 2018;Cai et al., 2020;Yau and McNally, 2018). Yet, the nature of fMRI measurements does not allow us to directly trace back the observed BOLD responses to the phasic firing of dopamine cells at the time of threat omission. ...
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The unexpected absence of danger constitutes a pleasurable event that is critical for the learning of safety. Accumulating evidence points to similarities between the processing of absent threat and the well-established reward prediction error (PE). However, clear-cut evidence for this analogy in humans is scarce. In line with recent animal data, we showed that the unexpected omission of (painful) electrical stimulation triggers activations within key regions of the reward and salience pathways and that these activations correlate with the pleasantness of the reported relief. Furthermore, by parametrically violating participants’ probability and intensity related expectations of the upcoming stimulation, we showed for the first time in humans that omission-related activations in the VTA/SN were stronger following omissions of more probable and intense stimulations, like a positive reward PE signal. Together, our findings provide additional support for an overlap in the neural processing of absent danger and rewards in humans.
... It is wellestablished that ventral midbrain DA neurons, located in the ventral tegmental area (VTA) and the substantia nigra (SN), encode reward prediction errors (RPE) which act as teaching signals to drive reinforcement learning [20][21][22][23][24] . Recent studies have further demonstrated that ventral midbrain DA neurons encode positive PE signals not only for rewards, but also for omission of aversive outcomes [25][26][27][28] to drive associative learning. Interestingly, dorsal tegmental DA neurons that project to the amygdala have recently been shown to encode a PE signal to mediate fear learning 29 . ...
... Consistent with these findings, in DA-deficient mice, restoring DA production specifically in projections to BLA and striatum reversed deficits in fear memory formation 47 . Furthermore, disrupting phasic firing in dopamine neurons has been shown to impair fear learning 48,49 ; and midbrain dopamine neurons exhibit phasic firing in response to aversive USs as well as CSs that predict them 16,25,29,35,[49][50][51][52][53][54][55][56] . Interestingly, recent studies showed that DA terminals in BLA are activated by both aversive and rewarding stimuli, suggesting that these DA neurons encode the motivational salience of stimuli 57,58 . ...
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Learning by experience that certain cues in the environment predict danger is crucial for survival. How dopamine (DA) circuits drive this form of associative learning is not fully understood. Here, in male mice, we demonstrate that DA neurons projecting to a unique subregion of the dorsal striatum, the posterior tail of the striatum (TS), encode a prediction error (PE) signal during associative fear learning. These DA neurons are necessary specifically during acquisition of fear learning, but not once the fear memory is formed, and are not required for forming cue-reward associations. Notably, temporally-precise inhibition or excitation of DA terminals in TS impairs or enhances fear learning, respectively. Furthermore, neuronal activity in TS is crucial for the acquisition of associative fear learning and learning-induced activity patterns in TS critically depend on DA input. Together, our results reveal that DA PE signaling in a non-canonical nigrostriatal circuit is important for driving associative fear learning.
... Since Raczka et al., backtranslational animal studies have demonstrated activity increases in dopaminergic VTA neurons projecting to the nucleus accumbens and phasic release of dopamine in the nucleus accumbens precisely at CS offsets, both of which decline over the course of extinction (Luo et al. 2018;Salinas-Hernández et al. 2018, 2023. The same dopamine neurons take part in a reward learning task, but are not sensitive to aversive stimulation (Salinas-Hernández et al. 2023). ...
... The same dopamine neurons take part in a reward learning task, but are not sensitive to aversive stimulation (Salinas-Hernández et al. 2023). Their activity is both necessary and sufficient to induce extinction learning (Luo et al. 2018;Salinas-Hernández et al. 2018, 2023. Also, systemic administration of the dopamine precursor L-DOPA before extinction in mice with an extinction learning deficit has been reproducibly shown to rescue extinction (Whittle et al. 2016;Sartori et al. 2024), further corroborating a role of dopamine in fear extinction. ...
Chapter
The elucidation of the functional neuroanatomy of human fear, or threat, extinction has started in the 2000s by a series of enthusiastically greeted functional magnetic resonance imaging (fMRI) studies that were able to translate findings from rodent research about an involvement of the ventromedial prefrontal cortex (vmPFC) and the hippocampus in fear extinction into human models. Enthusiasm has been painfully dampened by a meta-analysis of human fMRI studies by Fullana and colleagues in 2018 who showed that activation in these areas is inconsistent, sending shock waves through the extinction research community. The present review guides readers from the field (as well as non-specialist readers desiring safe knowledge about human extinction mechanisms) during a series of exposures with corrective information. New information about extinction-related brain activation not considered by Fullana et al. will also be presented. After completion of this exposure-based fear reduction program, readers will trust that the reward learning system, the cerebellum, the vmPFC, the hippocampus, and a wider brain network are involved in human fear extinction, along with the neurotransmitters dopamine and noradrenaline. Specific elements of our exposure program include exploitation of the temporal dynamics of extinction, of the spatial heterogeneity of extinction-related brain activation, of functional connectivity methods, and of large sample sizes. Implications of insights from studies in healthy humans for the understanding and treatment of anxiety-related disorders are discussed.
... Salinas-Hernandez et al. studied the involvement of DA neurons in the VTA in extinction of fear responses, as it is a critical aspect in adaptive behavior and its deficit in safety learning represents a trait in anxiety disorder. Using optogenetic approach, authors have found that inhibition of DA neurons firing at the time of the unconditioned stimulus (US) omission is necessary for the fear extinction learning, while enhancing DA neurons firing at the time of the US omission accelerates fear extinction learning [36]. ...
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Dopaminergic neurotransmission is involved in several important brain functions, such as motor control, learning, reward‐motivated behavior, and emotions. Dysfunctions of dopaminergic system may lead to the development of various neurological and psychiatric disorders, like Parkinson's disease, schizophrenia, depression, and addictions. Despite years of sustained research, it is not fully established how dopaminergic neurotransmission governs these important functions through a relatively small number of neurons that release dopamine. Light‐driven neurotechnologies, based on the use of small light‐regulated molecules or overexpression of light‐regulated proteins in neurons, have greatly contributed to the advancement of our understanding of dopaminergic circuits and our ability to control them selectively. Here, we overview the current state‐of‐the‐art of light‐driven control of dopaminergic neurotransmission. While we provide a concise guideline for the readers interested in pharmacological, pharmacogenetic, and optogenetic approaches to modulate dopaminergic neurotransmission, our primary focus is on the usage of photocaged and photo‐switchable small dopaminergic molecules. We argue that photopharmacology, photoswitchable molecules of varied modalities, can be employed in a wide range of experimental paradigms, providing unprecedent insights into the principles of dopaminergic control, and represent the most promising light‐based therapeutic approach for spatiotemporally precise correction of dopamine‐related neural functions and pathologies.
... Therefore, enhanced cholinergic signals may reduce the influence of BLA inputs carrying unsigned prediction errors via the activation of M1 receptors, thereby increasing the impact of others carrying signed prediction errors, such as dopamine inputs from the ventral tegmental area. Although some controversy exists on how dopamine neurons respond to aversiveness (Mirenowicz and Schultz, 1996;Fiorillo, 2013), several studies have reported that dopamine neurons are inhibited by unexpected threats (Matsumoto and Hikosaka, 2009;Matsumoto et al., 2016) and excited by unexpected threat omission (Salinas-Hernández et al., 2018). In addition, dopaminergic signals at the time of outcome modulate aversive learning (Luo et al., 2018;Vander Weele et al., 2018). ...
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