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Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes
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.
... 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. ...
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 . ...
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. ...
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]. ...
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). ...
Outcomes can vary even when choices are repeated. Such ambiguity necessitates adjusting how much to learn from each outcome by tracking its variability. The medial prefrontal cortex (mPFC) has been reported to signal the expected outcome and its discrepancy from the actual outcome (prediction error), two variables essential for controlling the learning rate. However, the source of signals that shape these coding properties remains unknown. Here, we investigated the contribution of cholinergic projections from the basal forebrain because they carry precisely timed signals about outcomes. One-photon calcium imaging revealed that as mice learned different probabilities of threat occurrence on two paths, some mPFC cells responded to threats on one of the paths, while other cells gained responses to threat omission. These threat- and omission-evoked responses were scaled to the unexpectedness of outcomes, some exhibiting a reversal in response direction when encountering surprising threats as opposed to surprising omissions. This selectivity for signed prediction errors was enhanced by optogenetic stimulation of local cholinergic terminals during threats. The enhanced threat-evoked cholinergic signals also made mice erroneously abandon the correct choice after a single threat that violated expectations, thereby decoupling their path choice from the history of threat occurrence on each path. Thus, acetylcholine modulates the encoding of surprising outcomes in the mPFC to control how much they dictate future decisions.
Retrieval can bring memories to a labile state, creating a window to modify its content during reconsolidation. Numerous studies have investigated this period to elucidate reconsolidation mechanisms, understand long-term memory persistence, and develop therapeutic strategies for memory-related psychiatric disorders. However, the temporal dynamics of post-retrieval memory processes have been largely overlooked, leading to mixed findings and hindering the development of targeted interventions. This review discusses retrieval-related cellular and molecular events and how they develop in series and parallel across time. Emerging evidence suggests that some mechanisms triggered after fear memory retrieval can influence either reconsolidation or persistence in different time windows. The temporal boundaries of these post-retrieval processes are still unclear. Further research integrating behavioral and molecular approaches to a deeper understanding of reconsolidation and persistence temporal dynamics is essential to address current debates, including which system/pathway offers the most effective therapeutic window of opportunity.
The extinction of conditioned fear responses is crucial for adaptive behavior, and its impairment is a hallmark of anxiety disorders such as posttraumatic stress disorder. Fear extinction takes place when animals form a new memory that suppresses the original fear memory. In the case of context-dependent fear memory, the new memory is formed within the reward-responding posterior subset of basolateral amygdala (BLA) that is genetically marked by Ppp1r1b ⁺ neurons. These memory engram cells suppress the activity of the original fear-responding Rspo2 ⁺ engram cells present in the anterior BLA, hence fear extinction. However, the neurological nature of the teaching signal that instructs the formation of fear extinction memory in the Ppp1r1b ⁺ neurons is unknown. Here, we demonstrate that ventral tegmental area (VTA) dopaminergic signaling drives fear extinction in distinct BLA neuronal populations. We show that BLA fear and extinction neuronal populations receive topographically divergent inputs from VTA dopaminergic neurons via differentially expressed dopamine receptors. Fiber photometry recordings of dopaminergic activity in the BLA reveal that dopamine (DA) activity is time-locked to freezing cessation in BLA fear extinction neurons, but not BLA fear neurons. Furthermore, this dopaminergic activity in BLA fear extinction neurons correlates with extinction learning. Finally, using projection-specific optogenetic manipulation, we find that activation of the VTA DA projections to BLA reward and fear neurons accelerated or impaired fear extinction, respectively. Together, this work demonstrates that dopaminergic activity bidirectionally controls fear extinction by distinct patterns of activity at BLA fear and extinction neurons.
Subjective relief from threat omission is emerging as a proxy index of reward Prediction Error signaling during safety learning. Yet, the relation between relief and prediction error signaling remains poorly understood, limiting translational research. Here, we complemented our previous research in this field by providing further evidence of similarities between the emotion of relief and prediction error signaling. To this end, we enrolled fifty-one healthy participants, and applied a Temporal Difference Learning approach to subjective relief ratings collected during a classical fear extinction learning paradigm. If relief is a reliable index of reward Prediction Error signal then it should display the classical backpropagation from unexpected reward delivery (unexpected threat omission) to conditioned cue presentation, as the large literature in reward learning clearly demonstrated across species. We found that a TD model largely fits subjective relief ratings. Future studies could thereby use this TD model to understand if and how relief-PE drive fear extinction and its potential deficit.
Dopamine neurons (DANs) play seemingly distinct roles in reinforcement, motivation, and movement, and DA-modulating therapies relieve symptoms across a puzzling spectrum of neurologic and psychiatric symptoms. Yet, the mechanistic relationship among these roles is unknown. Here, we show DA's tripartite roles are causally linked by a process in which phasic striatal DA rapidly and persistently recalibrates the propensity to move, a measure of vigor. Using a self-timed movement task, we found that single exposures to reward-related DA transients (both endogenous and exogenously-induced) exerted one-shot updates to movement timing--but in a surprising fashion. Rather than reinforce specific movement times, DA transients quantitatively changed movement timing on the next trial, with larger transients leading to earlier movements (and smaller to later), consistent with a stochastic search process that calibrates the frequency of movement. Both abrupt and gradual changes in external and internal contingencies--such as timing criterion, reward content, and satiety state--caused changes to the amplitude of DA transients that causally altered movement timing. The rapidity and bidirectionality of the one-shot effects are difficult to reconcile with gradual synaptic plasticity, and instead point to more flexible cellular mechanisms, such as DA-dependent modulation of neuronal excitability. Our findings shed light on how natural reinforcement, as well as DA-related disorders such as Parkinson's disease, could affect behavioral vigor.
Outcomes can vary even when choices are repeated. Such ambiguity necessitates adjusting how much to learn from each outcome by tracking its variability. The medial prefrontal cortex (mPFC) has been reported to signal the expected outcome and its discrepancy from the actual outcome (prediction error), two variables essential for controlling the learning rate. However, the source of signals that shape these coding properties remains unknown. Here, we investigated the contribution of cholinergic projections from the basal forebrain because they carry precisely timed signals about outcomes. One-photon calcium imaging revealed that as mice learned different probabilities of threat occurrence on two paths, some mPFC cells responded to threats on one of the paths, while other cells gained responses to threat omission. These threat- and omission-evoked responses were scaled to the unexpectedness of outcomes, some exhibiting a reversal in response direction when encountering surprising threats as opposed to surprising omissions. This selectivity for signed prediction errors was enhanced by optogenetic stimulation of local cholinergic terminals during threats. The enhanced threat-evoked cholinergic signals also made mice erroneously abandon the correct choice after a single threat that violated expectations, thereby decoupling their path choice from the history of threat occurrence on each path. Thus, acetylcholine modulates the encoding of surprising outcomes in the mPFC to control how much they dictate future decisions.
Accurately predicting an outcome requires that animals learn supporting and conflicting evidence from sequential experience. In mammals and invertebrates, learned fear responses can be suppressed by experiencing predictive cues without punishment, a process called memory extinction. Here, we show that extinction of aversive memories in Drosophila requires specific dopaminergic neurons, which indicate that omission of punishment is remembered as a positive experience. Functional imaging revealed co-existence of intracellular calcium traces in different places in the mushroom body output neuron network for both the original aversive memory and a new appetitive extinction memory. Light and ultrastructural anatomy are consistent with parallel competing memories being combined within mushroom body output neurons that direct avoidance. Indeed, extinction-evoked plasticity in a pair of these neurons neutralizes the potentiated odor response imposed in the network by aversive learning. Therefore, flies track the accuracy of learned expectations by accumulating and integrating memories of conflicting events.
Midbrain dopamine neurons are well known for their role in reward-based reinforcement learning. We found that the activity of dopamine axons in the posterior tail of the striatum (TS) scaled with the novelty and intensity of external stimuli, but did not encode reward value. We demonstrated that the ablation of TS-projecting dopamine neurons specifically inhibited avoidance of novel or high-intensity stimuli without affecting animals' initial avoidance responses, suggesting a role in reinforcement rather than simply in avoidance itself. Furthermore, we found that animals avoided optogenetic activation of dopamine axons in TS during a choice task and that this stimulation could partially reinstate avoidance of a familiar object. These results suggest that TS-projecting dopamine neurons reinforce avoidance of threatening stimuli. More generally, our results indicate that there are at least two axes of reinforcement learning using dopamine in the striatum: one based on value and one based on external threat.
Dopamine neurons are thought to encode novelty in addition to reward prediction error (the discrepancy between actual and predicted values). In this study, we compared dopamine activity across the striatum using fiber fluorometry in mice. During classical conditioning, we observed opposite dynamics in dopamine axon signals in the ventral striatum (‘VS dopamine’) and the posterior tail of the striatum (‘TS dopamine’). TS dopamine showed strong excitation to novel cues, whereas VS dopamine showed no responses to novel cues until they had been paired with a reward. TS dopamine cue responses decreased over time, depending on what the cue predicted. Additionally, TS dopamine showed excitation to several types of stimuli including rewarding, aversive, and neutral stimuli whereas VS dopamine showed excitation only to reward or reward-predicting cues. Together, these results demonstrate that dopamine novelty signals are localized in TS along with general salience signals, while VS dopamine reliably encodes reward prediction error.
Functional neuroanatomy of Pavlovian fear has identified neuronal circuits and synapses associating conditioned stimuli with aversive events. Hebbian plasticity within these networks requires additional reinforcement to store particularly salient experiences into long-term memory. Here we have identified a circuit that reciprocally connects the ventral periaqueductal gray and dorsal raphe region with the central amygdala and that gates fear learning. We found that ventral periaqueductal gray and dorsal raphe dopaminergic (vPdRD) neurons encode a positive prediction error in response to unpredicted shocks and may reshape intra-amygdala connectivity via a dopamine-dependent form of long-term potentiation. Negative feedback from the central amygdala to vPdRD neurons might limit reinforcement to events that have not been predicted. These findings add a new module to the midbrain dopaminergic circuit architecture underlying associative reinforcement learning and identify vPdRD neurons as a critical component of Pavlovian fear conditioning. We propose that dysregulation of vPdRD neuronal activity may contribute to fear-related psychiatric disorders.
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.
ELife digest
There are many types of learning; one type of learning means that rewards and punishments can shape future behavior. Dopamine is a molecule that allows neurons in the brain to communicate with one another, and it is released in response to unexpected rewards. Most neuroscientists believe that dopamine is important to learn from the reward; however, there are different opinions about whether dopamine is important to learn from punishments or not.
Previous studies that tried to examine how dopamine activities change in response to punishment have reported different results. One of the likely reasons for the controversy is that it was difficult to measure only the activity of dopamine-releasing neurons.
To overcome this issue, Matsumoto et al. used genetically engineered mice in which shining a blue light into their brain would activate their dopamine neurons but not any other neurons. Tiny electrodes were inserted into the brains of these mice, and a blue light was used to confirm that these electrodes were recording from the dopamine-producing neurons. Specifically if the electrode detected an electrical impulse when blue light was beamed into the brain, then the recorded neuron was confirmed to be a dopamine-producing neuron.
Measuring the activities of these dopamine neurons revealed that they were indeed activated by reward but inhibited by punishment. In other words, dopamine neurons indeed can signal punishments as negative and rewards as positive on a single axis. Further experiments showed that, if the mice predicted both a reward and a punishment, the dopamine neurons could integrate information from both to direct learning.
Matsumoto et al. also saw that when mice received rewards too often, their dopamine neurons did not signal punishment correctly. These results suggest that how we feel about punishment may depend on how often we experience rewards.
In addition to learning, dopamine has also been linked to many psychiatric symptoms such as addiction and depression. The next challenge will be to examine how the frequency of rewards changes an animal’s state and responses to punishment in more detail, and how this relates to normal and abnormal behaviors.
DOI: http://dx.doi.org/10.7554/eLife.17328.002
The amygdala, a critical structure for both Pavlovian fear conditioning and fear extinction, receives sparse but comprehensive dopamine innervation and contains dopamine D1 and D2 receptors. Fear extinction, which involves learning to suppress the expression of a previously learned fear, appears to require the dopaminergic system. The specific roles of D2 receptors in mediating associative learning underlying fear extinction require further study. Intra-basolateral amygdala (BLA) infusions of a D2 receptor agonist, quinpirole, and a D2 receptor antagonist, sulpiride, prior to fear extinction and extinction retention were tested 24 h after fear extinction training for long-term memory (LTM). LTM was facilitated by quinpirole and attenuated by sulpiride. In addition, A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor glutamate receptor 1 (GluR1) subunit, GluR1 phospho-Ser845, and N-methyl-D-aspartic acid receptor NR2B subunit levels in the BLA were generally increased by quinpirole and down-regulated by sulpiride. The present study suggests that activation of D2 receptors facilitates fear extinction and that blockade of D2 receptors impairs fear extinction, accompanied by changes in GluR1, GluR1-Ser845 and NR2B levels in the amygdala.
Generalized fear is a maladaptive behavior in which non-threatening stimuli elicit a fearful response. Here, we demonstrate that discrimination between predictive and non-predictive threat stimuli is highly sensitive to probabilistic discounting and increasing threat intensity in mice. We find that dopamine neurons of the ventral tegmental area (VTA) encode both the negative valence of threat-predictive cues and the certainty of threat prediction. As fear generalization emerges, the dopamine neurons that are activated by a threat predictive cue (CS+) decrease the amplitude of activation and an equivalent signal emerges to a non-predictive cue (CS-). Temporally precise enhancement of dopamine neurons during threat conditioning to high threat levels or uncertain threats can prevent generalization. Moreover, phasic enhancement of genetically captured dopamine neurons activated by threat cues can reverse fear generalization. These findings demonstrate the dopamine neurons reflect the certainty of threat prediction that can be used to inform and update the fear engram.
The relief from an aversive event is rewarding. Since organisms are able to learn which environmental cues can cease an aversive event, relief learning helps to better cope with future aversive events. Literature data suggest that relief learning is affected in various psychopathological conditions, such as anxiety disorders. Here, we investigated the role of the mesolimbic dopamine system in relief learning. Using a relief learning procedure in Sprague Dawley rats, we applied a combination of behavioral experiments with anatomical tracing, c-Fos immunohistochemistry, and local chemogenetic and pharmacological interventions to broadly characterize the role of the mesolimbic dopamine system. The present study shows that a specific part of the mesolimbic dopamine system, the projection from the posterior medial ventral tegmental area (pmVTA) to the nucleus accumbens shell (AcbSh), is activated by aversive electric stimuli. 6-OHDA lesions of the pmVTA blocked relief learning but fear learning and safety learning were not affected. Chemogenetic silencing of the pmVTA-AcbSh projection using the DREADD approach, as well as intra-AcbSh injections of the dopamine D2/3 receptor antagonist raclopride inhibited relief learning. Taken together, the present data demonstrate that the dopaminergic pmVTA-AcbSh projection is critical for relief learning but not for similar learning phenomena. This novel finding may have clinical implications since the processing of signals predicting relief and safety is often impaired in patients suffering from anxiety disorders. Furthermore, it may help to better understand psychological conditions like non-suicidal self-injury, which are associated with pain offset relief.
Anxiety disorders constitute the largest group of mental disorders in most western societies and are a leading cause of disability. The essential features of anxiety disorders are excessive and enduring fear, anxiety or avoidance of perceived threats, and can also include panic attacks. Although the neurobiology of individual anxiety disorders is largely unknown, some generalizations have been identified for most disorders, such as alterations in the limbic system, dysfunction of the hypothalamic-pituitary-adrenal axis and genetic factors. In addition, general risk factors for anxiety disorders include female sex and a family history of anxiety, although disorder-specific risk factors have also been identified. The diagnostic criteria for anxiety disorders varies for the individual disorders, but are generally similar across the two most common classification systems: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the International Classification of Diseases, Tenth Edition (ICD-10). Despite their public health significance, the vast majority of anxiety disorders remain undetected and untreated by health care systems, even in economically advanced countries. If untreated, these disorders are usually chronic with waxing and waning symptoms. Impairments associated with anxiety disorders range from limitations in role functioning to severe disabilities, such as the patient being unable to leave their home.