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Dopaminergic modulation of the neural circuitry underlying fear extinction. Schematic of the three major projections of the ventral tegmental area (VTA) dopamine (DA) neurons likely involved in fear extinction are shown. BLA, basolateral amygdala; EPE, extinction prediction error; IL, infralimbic cortex; ITCs, intercalated cell masses (dm: dorsomedial, vm: ventromedial); LC, locus coeruleus; NA, noradrenalin; NAc, nucleus accumbens. Question marks (?) indicate possible DAergic projections mediating fear extinction. The involvement of these projections in extinction remains to be tested. (A) A subset of VTA DA neurons encodes an EPE signal that is necessary to initiate fear extinction learning. The projection target of EPE encoding DA neurons is currently unknown. NAc constitutes an ideal candidate however the exact subregion of NAc receiving the EPE signal remains to be determined. (B) Activation of DA receptors in the BLA mediates the acquisition of fear extinction memories. However, the source of DA input to the amygdala during extinction has not directly been demonstrated. Whether VTA DA projections to the BLA and also likely to dmITCs, are involved in fear extinction is an important outstanding question. (C) DA is crucial for the consolidation of extinction memories in the IL. The source of DA input to IL during fear extinction has remained elusive, however, IL receives its main DA input from the VTA and IL-projecting VTA DA neurons are thus plausible candidates. However, recent studies suggest that this DA projection is pro-aversive; and thus, DA released from other sources, such as NA neurons located in the LC might be more likely to mediate fear extinction.
Source publication
The ability to extinguish fear memories when threats are no longer present is critical for adaptive behavior. Fear extinction represents a new learning process that eventually leads to the formation of extinction memories. Understanding the neural basis of fear extinction has considerable clinical significance as deficits in extinction learning are...
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Citations
... Thus, fear memory extinction represents new learning rather than simple forgetting (Jacques et al., 2019;Quirk, 2002, 2012;Morgan and LeDoux, 1995) by repeated exposure to the CS or fear-associated context in the absence of the US ( Figure 2D). The animals gradually learn that the CS is no longer associated with the US (electric footshock), and therefore, the previously learned fear behavior diminishes ( Figure 2E) Quirk, 2002, 2012;Salinas-Hernandez and Duvarci, 2021). Fear extinction is a form of safety learning, involving the formation of an inhibitory memory that competes with the original fear memory. ...
Introduction
Ketamine, a multimodal dissociative anesthetic, is widely used as a trauma analgesic in emergency situations. Ketamine is also used to treat psychiatric disorders due to its broad application potential, including treatment-resistant major depression. However, its impacts on the development of post-traumatic stress disorder (PTSD) and its potential as a treatment for PTSD are controversial. PTSD is marked by persistent and intrusive memories of traumatic event(s) and re-experiencing of the traumatic memories when exposed to trauma-related stimuli. Individuals with PTSD are often treated with prolonged exposure therapy (PE), in which they are gradually exposed to stimuli that remind them of the previous traumatic memory. If successful, they may learn that the previously traumatic stimuli are no longer threatening, a process known as fear extinction. Although fear extinction can be studied in laboratory animals, previous preclinical literature on the effects of ketamine on fear extinction has been inconsistent.
Methods
Thus, we summarized the existing preclinical literature examining effects of ketamine on fear extinction and its potential molecular mechanisms.
Results
Studies found that ketamine may enhance, impair, have no effect, or have mixed effects on fear extinction. These discrepancies may be attributed to differences in dosage, route, and timing of ketamine administration.
Discussion
We conclude the review with recommendations for future research on ketamine and PTSD such as the inclusion of more female subjects, clinically relevant doses and routes of ketamine administration, and more comprehensive behavioral assays that are relevant to PTSD in humans to enhance translation between preclinical and clinical research.
... It is possible that because we kept both the knockout and wildtype mice together, these two groups influenced each other, as mixed-group housing of knockout and wildtype mice was reported previously to affect behavior [78]. Recent work provides clear evidence of the importance of the VTA in fear extinction, with the VTA sending dopamine projections to other brain areas critically involved in fear extinction [79,80]. While recent work has focused on the dopamine-related neural circuitry of fear extinction, we know very little about the molecular pathways supporting the role of dopamine in this process. ...
Fear extinction leads to a decrease of originally acquired fear responses after the threat is no longer present. Fear extinction is adaptive and critical for organism’s survival, but deficits in extinction may lead to exaggerated fear in animals or post-traumatic stress disorder (PTSD) in humans. Dopamine has recently emerged as essential for fear extinction and PTSD, however the neural circuits serving this dopamine function are only beginning to be investigated, and the dopamine intracellular signaling pathways are unknown. We generated gastrin-releasing peptide gene knockout (Grp-/-) mice and found that they exhibit enhanced fear memory in a stress-enhanced fear learning (SEFL) paradigm, which combines stress exposure and fear extinction, two features critical for developing PTSD. Using in vivo fiber photometry to record dopamine signals, we found that the susceptibility of Grp-/- mice to SEFL is paralleled by an increase in basolateral amygdala (BLA) dopaminergic binding during fear conditioning and early extinction. Combined optogenetics and ex vivo electrophysiology showed an increase in presynaptic ventral tegmental area (VTA)-BLA connectivity in Grp-/- mice, demonstrating a role of dysregulated input from the VTA on BLA function in the absence of the GRP. When examining gene transcription using RNA-seq and qPCR, we discovered concerted down-regulation in dopamine-related genes in the BLA of Grp-/- mice following long-term SEFL memory recall that was not observed in naïve conditions. These experiments demonstrate that the GRP regulates dopamine function in stress-enhanced fear processing and identify the Grp as the first gene known to regulate dopaminergic control of fear extinction.
... Other theoretical work suggests that positively valenced systems are inextricably linked to threat processingfor example, the removal of threat can be an inherently rewarding experience (for a review, see Rosenberg, Barnes-Horowitz, et al., 2024). More specifically, striatal dopamine signals the unexpected omission of aversive outcomes during Pavlovian fear extinction (Kalisch et al., 2019;Gentry et al., 2019;Salinas-Hernández & Duvarci, 2021) corresponding with subjective experiences of relief (Willems et al., 2023), a positive emotion that is experienced as similarly rewarding compared with monetary gains (Leng et al., 2023) and is moderated by reward sensitivity (Leng et al., 2022(Leng et al., , 2024. The positively valenced experience of relief is thought to (1) reinforce escape from the predicted dangerous outcomes (unconditioned stimulus; US) or instrumental avoidance of the CS (Carver, 2009;Deutsch et al., 2015), and (2) coincide with prediction error learning when an anticipated fearful outcome surprisingly does not occur (i.e., during Pavlovian fear extinction) (Vervliet et al., 2017). ...
Background
Reward and threat processes work together to support adaptive learning during development. Adolescence is associated with increasing approach behavior (e.g., novelty-seeking, risk-taking) but often also coincides with emerging internalizing symptoms, which are characterized by heightened avoidance behavior. Peaking engagement of the nucleus accumbens (NAcc) during adolescence, often studied in reward paradigms, may also relate to threat mechanisms of adolescent psychopathology.
Methods
47 typically developing adolescents (9.9–22.9 years) completed an aversive learning task during functional magnetic resonance imaging, wherein visual cues were paired with an aversive sound or no sound. Task blocks involved an escapable aversively reinforced stimulus (CS+ r ), the same stimulus without reinforcement (CS+ nr ), or a stimulus that was never reinforced (CS−). Parent-reported internalizing symptoms were measured using Revised Child Anxiety and Depression Scales.
Results
Functional connectivity between the NAcc and amygdala differentiated the stimuli, such that connectivity increased for the CS+ r ( p = .023) but not for the CS+ nr and CS−. Adolescents with greater internalizing symptoms demonstrated greater positive functional connectivity for the CS− ( p = .041).
Conclusions
Adolescents show heightened NAcc-amygdala functional connectivity during escape from threat. Higher anxiety and depression symptoms are associated with elevated NAcc-amygdala connectivity during safety, which may reflect poor safety versus threat discrimination.
... A number of rodent studies support the role of dopaminergic processes in fear extinction as well. Specifically, a dopaminergic response has been identified during omission of an expected US av in fear extinction (Gentry et al., 2019;Kalisch et al., 2019;Salinas-Hernández & Duvarci, 2021). 5 Further, the magnitude of dopamine signaling has been associated with the strength of fear extinction learning, measured by conditional freezing behavior in mice (Salinas-Hernández et al., 2018). ...
... Activation of dopaminergic signaling immediately after fear extinction has been as- Rosenberg et al. Journal of Anxiety Disorders xxx (xxxx) 102911 sociated with enhanced extinction memory storage and retrieval (Kalisch et al., 2019;Salinas-Hernández & Duvarci, 2021). This set of animal findings suggests that omission of an expected US av during fear extinction shares biological processes with the unexpected occurrence of a US app during appetitive conditioning (Gentry et al., 2019). ...
... This set of animal findings suggests that omission of an expected US av during fear extinction shares biological processes with the unexpected occurrence of a US app during appetitive conditioning (Gentry et al., 2019). Furthermore, the basolateral amygdala (BLA) receives dopaminergic inputs from the ventral tegmental area and substantia nigra (Pezze & Feldon, 2004;Rosenkranz & Grace, 1999;Salinas-Hernández & Duvarci, 2021), and specific subpopulations of BLA neurons are associated with reward-seeking behaviors (Kim et al., 2016). In a study of fear extinction among mice, these same BLA neurons were further found to be both "necessary and sufficient" for storing of extinction memories, which has been posited as evidence that extinction memories may be stored as rewarding information . ...
... In fear extinction (CS+ presented repeatedly without US), neurons fire during initial shock-omissions, then diminish over repeated trials (J. Y. Lee et al., 2021;Ney et al., 2021;Salinas-Hernández et al., 2023;Salinas-Hernández & Duvarci, 2021), with the magnitude of these PE signals predicting successful extinction retention over subsequent days (Kalisch et al., 2019;Raczka et al., 2011;Salinas-Hernández et al., 2018). These systems are also directly implicated in the success of de novo (blank slate) safety learning via conditioned inhibition (A+/AX-), with VTA dopamine activity directly predicting fear suppression during summation test (Yau & McNally, 2022). ...
Safety learning involves associating stimuli with the absence of threats, enabling the inhibition of fear and anxiety. Despite growing interest in psychology, psychiatry, and neuroscience research, safety learning lacks a formal consensus definition, leading to inconsistent methodologies and varied results. Conceptualized as a form of inhibitory learning (conditioned inhibition), safety learning can be understood through formal learning theories, such as the Rescorla-Wagner and Pearce-Hall models. This review aims to establish a principled conceptualization of ‘Pavlovian safety learning’, identifying cognitive mechanisms that generate it safety, and boundary conditions that constrain it. Based on these observations, we define Pavlovian safety learning as an active associative process, where surprising threat- omission (safety prediction error) acts as a salient reinforcing event. Instead of producing neutral or non-aversive states, the safety learning process endows stimuli with positive association to ‘safety’. The resulting stimulus-safety memories counteract the influence of fear memories, promoting fear regulation, positive affect, and relief. We critically analyze traditional criteria of conditioned inhibition for their relevance to safety and propose areas for future innovation. A principled concept of Pavlovian safety learning may reduce methodological inconsistencies, stimulate translational research, and facilitate a comprehensive understanding of an indispensable psychological construct.
... In recent years, we and other research groups have demonstrated a role of the neurotransmitter dopamine (DA) in fear extinction (for recent reviews see [9][10][11]) as enhancing DA levels by systemic administration of the DA bio-precursor, L-DOPA, DA or the non-selective monoaminergic drug, methylphenidate, facilitates extinction memory consolidation in healthy humans [12][13][14][15] and extinction-competent rodents, such as the C57BL/6 J (BL6) mouse strain [12,[16][17][18]. However, the neural loci of L-DOPA's effects on extinction are only now beginning to be unravelled [13,15,19,20]. ...
... These behaviour-related mPFC DA levels were augmented by systemic L-DOPA administration, in line with a previous finding in rats tested in a cocaine-seeking procedure [55]. These data are notable because although the vmPFC/IL is strongly implicated in fear extinction, prior work had not determined a causal contribution of DA neurotransmission in this brain region to fear extinction (for review see [9,11]). ...
The ventromedial prefrontal cortex (vmPFC; rodent infralimbic cortex (IL)), is posited to be an important locus of fear extinction-facilitating effects of the dopamine (DA) bio-precursor, L-DOPA, but this hypothesis remains to be formally tested. Here, in a model of impaired fear extinction (the 129S1/SvImJ inbred mouse strain; S1), we monitored extracellular DA dynamics via in vivo microdialysis in IL during fear extinction and following L-DOPA administration. Systemic L-DOPA caused sustained elevation of extracellular DA levels in IL and increased neuronal activation in a subpopulation of IL neurons. Systemic L-DOPA enabled extinction learning and promoted extinction retention at one but not ten days after training. Conversely, direct microinfusion of DA into IL produced long-term fear extinction (an effect that was insensitive to ɑ-/ß-adrenoreceptor antagonism). However, intra-IL delivery of a D1-like or D2 receptor agonist did not facilitate extinction. Using ex vivo multi-electrode array IL neuronal recordings, along with ex vivo quantification of immediate early genes and DA receptor signalling markers in mPFC, we found evidence of reduced DA-evoked mPFC network responses in S1 as compared with extinction-competent C57BL/6J mice that were partially driven by D1 receptor activation. Together, our data demonstrate that locally increasing DA in IL is sufficient to produce lasting rescue of impaired extinction. The finding that systemic L-DOPA increased IL DA levels, but had only transient effects on extinction, suggests L-DOPA failed to reach a threshold level of IL DA or produced opposing behavioural effects in other brain regions. Collectively, our findings provide further insight into the neural basis of the extinction-promoting effects of DA and L-DOPA in a clinically relevant animal model, with possible implications for therapeutically targeting the DA system in anxiety and trauma-related disorders.
... This behavioral finding is reminiscent of results of fear conditioning experiments following repeated exposure to cocaine in adult rats (15). Enhanced fear conditioning is associated with anxiety disorders (39), and prior work showed enhancement of anxiety-like behaviors in male cocainesired rats (25). Although conditioned freezing is the most commonly assessed adaptive fear response in rodents, recent studies revealed the presence of an active fear response known as darting, which develops in some animals that undergo fear conditioning (33,34). ...
Cocaine self-administration by male rats results in neuronal and behavioral alterations in offspring, including responses to cocaine. Given the high degree of overlap between the brain systems underlying the pathological responses to cocaine and stress, we examined whether sire cocaine taking would influence fear-associated behavioral effects in drug-naïve adult male and female progeny. Sire cocaine exposure had no effect on contextual fear conditioning or its extinction in either male or female offspring. During cued fear conditioning, freezing behavior was enhanced in female, but not male, cocaine-sired progeny. In contrast, male cocaine-sired progeny exhibited enhanced expression of cue-conditioned fear during extinction. Long-term potentiation (LTP) was robust in the basolateral amygdala (BLA), which encodes fear conditioning, of female offspring but was completely absent in male offspring of cocaine-exposed sires. Collectively, these results indicate that cued fear memory is enhanced in the male progeny of cocaine exposed sires, which also have BLA synaptic plasticity deficits.
... Once the animal has learned the fear response (i.e., freezing upon CS), the fear memory and reaction have been consolidated. The animal will now produce that behavior when the CS is presented [73,74]. The entire response has been acquired by associating the CS with the US. ...
... The fear extinction process is something of the reverse of this in which the CS is repeatedly presented to the animal, but the US is absent. Over time, the animal learns that it is safe and no longer produces the fear response [73,74]. The animal models have proven to be generalizable to human fear conditioning as well. ...
... Linkages have been made between the neurological systems involved, dopamine and the gut microbiome, which all play into these learned behaviors. Salinas-Hernández and Duvarci [74] stress that fear extinction appears to represent new learning rather than forgetting or erasure of the original fear memory, and that it may be promoted by the reward learning system. In their model, midbrain dopamine neurons encode reward prediction error (RPE) signals to drive reward learning [74]. ...
Balanced fear supports human rational decision-making and useful behavioral responses. In contrast, overwhelming, persistent, and unbalanced fear can paralyze the individual and result in heightened anxiety, lack of cognitive flexibility, fear-based public compliance and serious mental health issues. Psychobiotics research has established that a healthy microbiome is required for balanced fear and mental health protection via control of fear extinction. The recent COVID-19 pandemic featured daily, persistent, fear-of-a-single-contagion conditioning on a global scale paired with various behavioral mandates (e.g., lockdowns of the healthy, required wearing of face masks in many locations including schools, isolation from environmental microbes and each other through the closure of beaches and parks, and restrictions on social gatherings including access to family members in hospitals and senior-assisted facilities). Such mandates degraded the human microbiome and isolated us from each other and useful environmental microbes. It also ignored the historic role of secondary bacterial pathogens in pandemic deaths. This narrative review examines how the institutional promotion of fear-of-a-single-contagion, lack of balanced risk communication, and appalling disregard of our fundamental nature (as majority-microbial human superorganisms) resulted in problems rather than solutions. This review illustrates that government-public health-media promotion of pervasive fear and microbiome-degrading behaviors: (1) increased public compliance, (2) reduced cognitive flexibility, and (3) increased risk of mental health conditions. However, a portion of the general public chose a healthier path through their increased consumption of microbiome- and immune-supportive supplements and fermented foods during and after the COVID-19 pandemic. For a healthier future, public health must follow the lead of this population to ensure that human freedom, rather than paralyzing fear, dominates our future.
... Once the animal has learned the fear response (i.e., freezing upon CS), the fear memory and reaction have been consolidated. The animal will now produce that behavior when the CS is presented [73,74]. The entire response has been acquired by associating the CS with a US. ...
... The fear extinction process is something of the reverse of this in which the CS is repeatedly presented to the animal, but the US is absent. Over time the animal learns that it is safe and no longer produces the fear response [73,74]. The animal models have proven to be generalizable to human fear conditioning as well. ...
... Linkages have been made between the neurological systems involved, dopamine and the gut microbiome, which all play into these learned behaviors. Salinas-Hernández and Duvarci [74] stress that fear extinction appears to represent new learning rather than forgetting or erasure of the original fear memory, and that it may be promoted by the reward learning system []. In their model, midbrain dopamine neurons encode reward prediction error (RPE) signals to drive reward learning [74]. ...
Balanced fear supports human rational decision making and useful behavioral responses. In contrast, overwhelming, persistent, and unbalanced fear can paralyze the individual and result in heightened anxiety, lack of cognitive flexibility, fear-based public compliance and serious mental health issues. Psychobiotics research has established that a healthy microbiome is required for balanced fear and mental health protection via control of fear extinction. The recent Covid-19 pandemic featured daily, persistent, fear-of-a single contagion conditioning on a global scale paired with various behavioral mandates (e.g., lockdowns of the healthy, masks, isolation from environmental microbes and each other) that degraded the human microbiome and isolated us from each other and useful environmental microbes. It also ignored the historic role of secondary bacterial pathobionts, in pandemic deaths. This narrative review examines how institutional promotion of fear-of-a single contagion, lack of balanced risk communication, and appalling disregard of our fundamental nature (as majority-microbial human superorganisms) resulted in problems rather than solutions. This review concludes that government-public health-media promotion of pervasive fear and microbiome-degrading behaviors: 1) increased public compliance, 2) reduced cognitive flexibility, and 3) increased risk of mental health conditions. It further argues that microbiome-first public health should be embraced to ensure that human freedom, rather than paralyzing fear, dominates our future.
... This group of cells constitutes the mesolimbic and mesocortical pathways, which is known to be involved in reward-related reinforcement, incentive salience, aversion-related cognition, and decision-making [45,46]. Therefore, abundant experimental studies have reported on the anatomical correlation between dopaminergic neurons in the VTA and the synaptic circuit involved in PTSD (PFC-AMY-HC) [41], which is crucial for the regulatory role of these neurons in fear memory formation [47], consolidation [48][49][50], and extinction [51][52][53]. Here, we focus on the experimental evidence of the relationship between the dopamine system and PTSD, thus we begin with a discussion of these clear results as the cutting-in point and summarize the scientific evidence indicating the neuroanatomy and functional links of the VTA-PFC, VTA-AMY, and VTA-HC to support our viewpoint. ...
... By blocking the feed-forward inhibition from nearby interneurons, dopamine regulates the production of long-term potential in the lateral AMY of mice [65]. Dopamine in the AMY mediates fear extinction [53]. A study reported that 24 h before fear extinction and extinction retention, intra-basolateral AMY infusions of a D2 receptor agonist, quinpirole, inhibited long-term memory, and infusion of a D2 receptor antagonist, sulpiride, promoted it [66]. ...
Posttraumatic stress disorder (PTSD) is a neuropsychiatric disease closely related to life-threatening events and psychological stress. Re-experiencing, hyperarousal, avoidance, and numbness are the hallmark symptoms of PTSD, but their underlying neurological processes have not been clearly elucidated. Therefore, the identification and development of drugs for PTSD that targets brain neuronal activities have stalled. Considering that the persistent fear memory induced by traumatic stimulation causes high alertness, high arousal, and cognitive impairment of PTSD symptoms. While the midbrain dopamine system can affect physiological processes such as aversive fear memory learning, consolidation, persistence, and extinction, by altering the functions of the dopaminergic neurons, our viewpoint is that the dopamine system plays a considerable role in the PTSD occurrence and acts as a potential therapeutic target of the disorder. This paper reviews recent findings on the structural and functional connections between ventral tegmental area neurons and the core synaptic circuits involved in PTSD, gene polymorphisms related to the dopamine system that confer susceptibility to clinical PTSD. Moreover, the progress of research on medications that target the dopamine system as PTSD therapies is also discussed. Our goal is to offer some hints for early detection and assist in identifying novel, efficient approaches for treating PTSD.
