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Fear Extinction as a Model for Translational Neuroscience: Ten Years of Progress
Abstract
The psychology of extinction has been studied for decades. Approximately 10 years ago, however, there began a concerted effort to understand the neural circuits of extinction of fear conditioning, in both animals and humans. Progress during this period has been facilitated by a high degree of coordination between rodent and human researchers examining fear extinction. Here we review the major advances and highlight new approaches to understanding and exploiting fear extinction. Research in fear extinction could serve as a model for translational research in other areas of behavioral neuroscience.
... One reason for this poor efficacy is that many patients face difficulties during the process of fear extinction. Fear extinction refers to the process by which a conditioned fear response gradually weakens when a previously feared stimulus is repeatedly presented without any negative consequences (Bouton, 2002;Milad & Quirk, 2012;Pavlov, 1927). Therefore, studying the factors that lead to difficulties in fear extinction is important for understanding the etiology of anxiety disorders and may provide new insights and methods for improving clinical intervention strategies. ...
... Fear extinction is a core process in the fear conditioning paradigm, a classical model for studying fear learning and its neural mechanisms (Pavlov, 1927). The fear conditioning paradigm consists of three key stages: fear acquisition, fear extinction, and fear reinstatement (Bouton & King, 1983;Milad & Quirk, 2012). During the fear acquisition phase, individuals repeatedly pair a neutral cue (conditioned stimulus, CS, e.g. ...
... shock), leading to the formation of a conditioned fear response. When the CS is later presented alone without the US, the conditioned fear response gradually diminishes, a process known as fear extinction (Bouton & Moody, 2004;LeDoux, 2000;Milad & Quirk, 2012;Pavlov, 1927). Importantly, fear extinction does not erase the original fear memory, but rather forms a new extinction memory, whereby the individual learns through a new process that the CS no longer predicts threat (Bouton, 1993;Bouton & King, 1983;Craske et al., 2014). ...
Conditioned fear learning is crucial for survival, and failure of fear extinction is closely related to the development of anxiety disorders. This study explores how different executive function (EF) subcomponents—shifting, updating, and inhibition—modulate conditioned fear extinction and reinstatement at both behavioral and neural levels. A total of 88 participants (age range: 17–23 years) completed the Stroop Task, Digit Size-Parity Switching Task, and Memory Updating Task to assess their executive function abilities. Participants underwent a classical fear extinction paradigm while their shock expectancy ratings and prefrontal cortical activity were recorded using functional near-infrared spectroscopy (fNIRS). Results indicated that individuals with higher shifting ability exhibited greater fear expectancy during fear acquisition (β = -0.406, p = 0.032) and reinstatement (β = -0.834, p = 0.004), along with higher prefrontal cortex activity (p < 0.05), suggesting heightened responses to threatening stimuli. Individuals with higher updating ability showed a slower decrease in fear expectancy during the early extinction phase (β = 0.038, p = 0.002), but maintained lower expectancy during the extinction recall phase (β = -0.769, p = 0.006), indicating poorer extinction learning but better extinction memory retention. Individuals with higher updating ability also exhibited more extinction recall in the prefrontal cortex regions (ps < 0.045). Individuals with higher inhibitory ability showed higher expectancy for CS+ and lower expectancy for CS− during extinction learning (β = -0.409, p = 0.008), along with a slower decrease in fear expectancy (β = -0.022, p = 0.055). Furthermore, individuals with higher inhibition ability showed lower PFC activity in immediate extinction (ps < 0.0421), suggesting slower extinction learning but better regulation of safety cues. By clarifying the roles of these executive function components, our study highlights the cognitive mechanisms that could inform interventions aimed at improving fear extinction, offering potential strategies for mitigating anxiety-related disorders.
... For instance, when rodents are repeatedly exposed to a previously threat-signaling stimulus that is now no longer associated with aversive consequences (extinction), fear responses decline due to increased transmission in the basolateral amygdala, which invokes an inhibition of the central amygdala that orchestrates multi-level fear responses [9,10]. Such fear extinction is considered to be the core mechanism of exposure-based treatments [4,8,11,12], and can even persist over longer time periods, if the medial prefrontal cortex activates the basolateral amygdala during future encounters of the previous threat cue [13,14]. Preclinical functional imaging research suggested, that the human amygdala and medial prefrontal cortex exhibit similar functions during fear extinction as in rodents [12,[15][16][17][18]. Accordingly, a technique that taps into these neural circuits might be a promising adjunct to facilitate responding to exposure-based treatments. ...
... Such fear extinction is considered to be the core mechanism of exposure-based treatments [4,8,11,12], and can even persist over longer time periods, if the medial prefrontal cortex activates the basolateral amygdala during future encounters of the previous threat cue [13,14]. Preclinical functional imaging research suggested, that the human amygdala and medial prefrontal cortex exhibit similar functions during fear extinction as in rodents [12,[15][16][17][18]. Accordingly, a technique that taps into these neural circuits might be a promising adjunct to facilitate responding to exposure-based treatments. ...
... Finally, the fear-attenuating effects of taVNS maintained 24 h after the stimulation was applied. This is consistent with previous literature, showing that vagal stimulation activates projection targets of the locus coeruleus noradrenergic system, not only including subcortical amygdala-circuits [19], but also the medial prefrontal cortex (mPFC) [20] an area, shown to critically mediate the consolidation and retention of fear extinction memory [12,15,98]. Our data therefore indicate that taVNS facilitated fear inhibition by tapping into the BLA, and consolidated fear- Fig. 6 Sensitized startle reflexes are associated with responding to in-vivo exposure. ...
Recent laboratory research showed that vagus nerve stimulation promotes fear extinction, the inhibitory core mechanism of exposure treatment, presumably via activation of the noradrenergic brain system. However, a translation of this stimulation technique to clinical practice is lacking. We therefore investigated the potential of vagal stimulation to inhibit excessive fear responses and facilitate responding to in-vivo and laboratory exposure in individuals with specific phobia. Spider-phobic participants were subjected to three standardized in-vivo exposures towards a living tarantula, complemented by an exposure in vitro (between exposure in vivo I and II). Transcutaneous auricular vagus nerve stimulation (taVNS) was applied during in-vitro exposure, presenting pictures of the exposed tarantula, other spiders and neutral tools in the laboratory. Fear was assessed by self-reports and behavioral avoidance (in-vivo exposures), and amygdala-mediated autonomic and behavioral fear components (exposure in vitro). Vagal stimulation facilitated the reduction of behavioral avoidance across repeated in-vivo exposures. During laboratory exposure, taVNS inhibited fear tachycardia and corrugator muscle activity specifically in response to pictures of the previously exposed tarantula – an effect that became stronger with increasing stimulation duration. Psychophysiological indices of noradrenergic transmission in the basolateral amygdala were elevated during taVNS and correlated to subsequent attenuation of behavioral avoidance. Our results suggest, that taVNS exerts stimulus-specific and dose-dependent inhibition of multiple automatic response components of excessive fear, highlighting taVNS as a valuable adjunct to exposure-based treatment. A translational mechanism of action is supported, proposing that taVNS exhibits its effects by noradrenergic activation of fear extinction circuitry, particularly targeting the basolateral amygdala.
... ;https://doi.org/10.1101https://doi.org/10. /2025 dorsolateral (dlPFC) and ventromedial prefrontal cortex (vmPFC) (for detailed reviews, refer to Sehlmeyer et al., 2009;Milad & Quirk, 2012;Fullana et al., 2016Fullana et al., , 2018Bouton et al., 2021). Here, the amygdala and vmPFC are crucial for processes involved in acquiring and extinguishing fear responses, including neuroplasticity. ...
... For example, hyperactivity of the amygdala during fear acquisition (Bremner et al., 2005;Marin et al., 2017) and extinction (Milad et al., 2009), as well as hypoactivation of the vmPFC during extinction recall (Marin et al., 2017), have been reported. Additionally, disrupted functional connectivity between the amygdala and vmPFC suggests reduced emotional regulation, further implicating the relevance of these regions for the development and maintenance of ADs (Hilbert et al., 2014;Milad et al., 2012Milad et al., , 2014. ...
... The results of the present study align with those findings. Mechanistically, the vmPFC/IL, which was upregulated in the present study by anodal tDCS, has been consistently shown to be involved in fear extinction, with a proposed mechanism involving top-down inhibition of the amygdala, leading to reduced fear responses (Milad et al., 2007;Milad & Quirk, 2012). Furthermore, inducing LTP-was not certified by peer review) is the author/funder. ...
Anxiety disorders (ADs) are among the most prevalent mental health conditions, yet first-line treatments often yield only moderate effectiveness. The fear conditioning paradigm is commonly used to investigate fear and extinction learning, revealing deficits in these processes and dysfunctional activity in the ventromedial prefrontal cortex (vmPFC) and amygdala in individuals with ADs. The vmPFC plays a critical role in regulating activity of the amygdala and consolidation of fear extinction memory. Notably, transcranial direct current stimulation (tDCS) has shown promise in enhancing fear extinction by modulating vmPFC activity. Additionally, rapid eye movement (REM) sleep has been suggested to be crucial for fear extinction memory consolidation.
This study investigated the role the vmPFC during REM sleep in fear extinction memory consolidation. Thirty-two participants underwent a 3-day differential fear conditioning paradigm, with tDCS or sham stimulation applied during REM sleep over the vmPFC. Outcome measures included skin conductance responses (SCR) and subjective ratings of arousal, fear, and valence. Results indicate that tDCS during REM sleep enhances fear extinction memory consolidation, as measured by SCR. Furthermore, participants reported an increased subjective arousal following tDCS. These findings suggest that tDCS during REM sleep may hold potential for improving exposure-based treatments for ADs by strengthening fear extinction memory.
... Interestingly, a recent study demonstrated that tone-fear conditioning and extinction, bi-directionally modulate spine morphology in activated ensemble neurons within the auditory cortexlateral amygdala circuit 13 , which may be directly related to changes in synaptic potentiation observed here. Nevertheless, our findings do not rule out the possibility of extinction-specific synaptic plasticity occurring elsewhere in the circuit, as demonstrated by other studies 38,39 . Instead, our work suggests that extinction might involve not only new learning but also unlearning of the original memory. ...
The nature and distribution of the synaptic changes that underlie memory are not well understood. Here we examine the synaptic plasticity behind context fear conditioning in male and female mice and find that new learning produces synaptic potentiation specifically onto engram neurons in the basolateral amygdala. This potentiation lasts at least 7 days, is reversed by extinction, and its disruption impairs memory recall. High frequency optogenetic stimulation of the CS and US-activated ensembles, or biochemical induction of synaptic potentiation in US-responsive neurons alone, is sufficient to produce a context fear association without prior associative training. These results suggest that plasticity of CS inputs onto US-responsive amygdala neurons underlies memory formation and is necessary and sufficient to establish context fear associations.
... Traumatic events or intense emotional experiences can result in the formation of pathological fear memories [1]. Cognitivebehavioral therapies including prolonged exposure therapy seek to extinguish maladaptive fear responses by exposing patients to trauma reminders in a safe environment [2,3]. Though effective, many patients are susceptible to relapse [4]. ...
Extinction learning is central to behavioral therapies for post-traumatic stress disorder (PTSD), but relapse poses a major challenge to this approach. Recent work has revealed a critical role for the thalamic nucleus reuniens (RE) in the suppression of extinguished fear memories. Silencing the RE yields a relapse of extinguished fear (i.e., “circuit-induced relapse”). Considerable work suggests that RE may contribute to extinction by inhibiting the retrieval of hippocampal (HPC)-dependent fear memories. To test this hypothesis, we first examined whether undermining the formation of contextual fear memories in the HPC would prevent circuit-induced relapse. Intra-hippocampal infusions of the NMDA receptor antagonist, APV, prior to auditory fear conditioning eliminated contextual fear memory and prevented the subsequent relapse of extinguished fear to the auditory conditioned stimulus (CS). In a second experiment, we used an activity-dependent labeling system (AAV-cFos-tTA; AAV-TRE-hM3Dq-mCherry) to express excitatory DREADDs in HPC neurons during fear conditioning. Chemogenetic reactivation of these ensembles after extinction was sufficient to drive relapse of fear to the extinguished CS. Lastly, in a third experiment, we expressed excitatory DREADDs in HPC ensembles captured during extinction learning and found that chemogenetic reactivation of this ensemble was sufficient to inhibit circuit-induced relapse. These results reveal that HPC-dependent ensembles play a critical role in regulating the expression and relapse of extinguished fear.
... During extinction, the mPFC is known to inhibit the amygdala which is also modulated by hippocampus 13 . In humans, functional connectivity studies have demonstrated coupling between amygdala, vmPFC and hippocampus during both fear expression and fear extinction 4,14 . Abnormal functioning in the hippocampal-prefrontal-amygdala network has been associated with impaired emotion regulation and posttraumatic stress disorder (PTSD) 15,16 . ...
Fearful memories can be extinguished by repeated exposure, without aversive outcomes. Fear extinction as the basis for exposure therapy, is a common treatment for anxiety and fear-related disorders, but it can be unpleasant and does not always work. In two independent studies, we investigated whether a novel compound extinction procedure (simultaneous presentation of a rewarded and a feared stimulus, reward–fear deepened extinction) attenuates fear while tracking physiological, neural and subjective changes in pleasantness. The reward–fear deepened extinction showed comparable effects to the fear–fear deepened extinction (two-fear compound extinction) in effectively enhancing fear extinction and protecting against the return of fear 1 week later. Moreover, fear extinction accompanying a reward cue was perceived as more pleasant. On the neural level, we identified a network involving hippocampus and amygdala that underlies the benefit of deepened extinction, where connectivity changes also predicted changes in subjective pleasantness. Our study identifies the effects of deepened extinction in regulating long-term fear recovery and its underlying neural mechanism. We shed light on an innovative method to enhance fear extinction, with high translational potential for therapy.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-025-99758-3.
... BAe neurons receive input from the infralimbic subdivision (IL) of the medial prefrontal cortex (mPFC) and are essential for extinction learning, increasing in activity as CS responses fade in the absence of the US, coupled with reduced BAf neuron activity (Herry et al., 2008). These shifts in neuronal activity are associated with reduced fear expression and increased CS approach behaviors (Milad & Quirk, 2012). Evidence suggests that BAf and BAe neural groups are mutually inhibiting ( Figure 1) (Janak & Tye, 2015;Kim et al., 2016;Pare & Duvarci, 2012). ...
Background
A connection between stress‐related illnesses and alcohol use disorders is extensively documented. Fear conditioning is a standard procedure used to study stress learning and links it to the activation of amygdala circuitry. However, the connection between the changes in amygdala circuitry and function induced by alcohol and fear conditioning is not well established.
Methods
We introduce a computational model to test the mechanistic relationship between amygdala functional and circuit adaptations during fear conditioning and the impact of acute vs. repeated alcohol exposure. Using firing rate formalism, the model generates electrophysiological and behavioral responses in fear conditioning protocols via plasticity of amygdala inputs. The influence of alcohol is modeled by accounting for known modulation of connections within amygdala circuits, which consequently affect plasticity. Thus, the model connects the electrophysiological and behavioral experiments. We hypothesize that alterations within amygdala circuitry produced by alcohol cause abnormal plasticity of amygdala inputs such that fear extinction is slower to achieve and less robust.
Results
In accordance with prior experimental results, both acute and prior repeated alcohol decrease the speed and robustness of fear extinction in our simulations. The model predicts that, first, the delay in fear extinction caused by alcohol is mostly induced by greater activation of the basolateral amygdala (BLA) after fear acquisition due to alcohol‐induced modulation of synaptic weights. Second, both acute and prior repeated alcohol shift the amygdala network away from the robust extinction regime by inhibiting activity in the central amygdala (CeA). Third, our model predicts that fear memories formed during acute or after chronic alcohol are more connected to the context.
Conclusions
The model suggests how circuit changes induced by alcohol may affect fear behaviors and provides a framework for investigating the involvement of multiple neuromodulators in this neuroadaptive process.
... This process, termed extinction training, creates an extinction memory trace that is distinct from the original fear memory formed during fear acquisition, in which the CS + no longer predicts the occurrence of the UCS. This extinction memory competes with the fear memory for expression when the extinguished stimulus (CS + E) is once again presented [9,29]. The magnitude of extinction memory retention (that is, the strength of the new CS + / UCS association) has typically been operationalized as the degree to which participants are no longer subjectively and physiologically reactive to the CS + E following a retention delay. ...
Purpose of Review
Sleep disturbances are common in anxiety disorders. Sleep is critical for extinction memory consolidation, a process central to exposure therapy. Here we review basic, clinical, and translational research to clarify sleep’s role in processing extinction memories, including in the context of exposure therapy.
Recent Findings
Sleep plays a significant role in extinction memory retention. Poor sleep quality predicts worse anxiety disorder treatment outcomes. Studies in specific phobia and social anxiety disorder indicate that the memory consolidation effects of sleep can be leveraged to enhance the retention of extinction memories during exposure therapy. Whether targeted memory cuing during NREM and/or REM sleep following exposure may further facilitate this enhancing effect is unclear.
... Similarly, providing clear, age-appropriate explanations reduces uncertainty by engaging the hippocampus for memory formation [54] and the temporal lobe for language comprehension [55]. This process prevents the unnecessary activation of the amygdala, helping the child feel more secure [56]. ...
Cultural norms, beliefs, and practices influence parental expectations, children’s responses, and the acceptance of behaviour management techniques (BMTs) in paediatric dentistry. Despite this, the existing guidelines often adopt a standardized approach, overlooking critical cultural differences. This scoping review maps the links between culture and behaviour management strategies in paediatric dental settings. A scoping review following PRISMA guidelines was conducted across PubMed, Cochrane Library, Web of Science, Google Scholar, and hand-searched sources from the inception of the databases to 31 January 2025. A total of 671 studies were identified, with 15 meeting the inclusion criteria. Data on the key findings were inductively analyzed to assess cultural influences on parental acceptance, child behavior, and communication. The findings show that non-invasive BMTs such as TellShow–Do and positive reinforcement were the most accepted across cultures, while passive and active restraints were least accepted, especially in Western populations. Parental preferences varied; Jordanian parents were more accepting of passive restraint than German parents, while general anaesthesia was preferred in Bahrain. Cultural norms shaped communication styles—Latino families emphasized warm interpersonal interactions, whereas Pakistani families exhibited limited parental involvement due to language barriers. Black and Hispanic Medicaid-enrolled mothers in the U.S. reported lower satisfaction with pain management, highlighting disparities in culturally competent care. In conclusion, cultural factors significantly influence paediatric behaviour management in dental clinics. Integrating cultural competence into practice can enhance communication, improve patient compliance, and promote equitable care. Further research is needed, particularly in Africa and South America, to inform globally inclusive behaviour management guidelines.
... Learning to identify and react to threatening situations is essential for survival, but it is equally vital to adjust the behavioral responses when those stimuli are no longer associated with danger 1 . The inability to extinguish fearful memories is an inherent aspect of many anxiety disorders such as post-traumatic stress disorder and phobias 2,3 . A widely used experimental approach to study learned fear responses and their subsequent extinction is based on Pavlovian conditioning 4 . ...
The ability to extinguish learned fear responses is crucial for adaptive behavior. The mesolimbic dopaminergic system originating in the ventral tegmental area has been proposed to contribute to fear extinction learning because of its critical role in reward learning. The unexpected omission of aversive unconditioned stimuli (US) is considered as rewarding (outcome better than expected) and to drive extinction learning. We tested the hypothesis that extinction learning is facilitated by dopaminergic drugs and impeded by anti-dopaminergic drugs. The effects of dopamine agonists [levodopa (100 mg) and bromocriptine (1.25 mg)] and antagonists [tiapride (100 mg) and haloperidol (3 mg)] on fear extinction learning were compared to placebo in 146 young and healthy human participants. A three-day differential fear conditioning paradigm was performed with pupil size and skin conductance responses (SCRs) being recorded. Fear acquisition training was performed on day 1, extinction training on day 2, and recall was tested on day 3. The conditioned stimuli (CS+, CS-) consisted of two geometric figures. A short electrical stimulation was used as the aversive US. One of the four drugs or placebo was administered prior to the extinction phase on day 2. Overall, effects were small and seen only in the bromocriptine group. In line with our hypothesis, we measured reduced pupil dilation during late recall in the bromocriptine group compared to the placebo group, indicating faster re-extinction of spontaneously recovered fear reactions on the third day. Effects of levodopa and haloperidol were unspecific and related to generally increased SCR levels in the levodopa group (already prior to drug intake), and miotic side-effects of haloperidol. Findings provide additional support that the dopaminergic system contributes to extinction learning in humans, possibly by improving consolidation of fear extinction memory.
... For example, the amygdala, a key region involved in emotional processing, has been shown to exhibit heightened activation during fear acquisition, primarily during the early phase of conditioning (Buchel et al., 1999;LaBar et al., 1998;Phelps, 2004). The amygdala's engagement in fear acquisition has been debated in more recent studies (Visser et al., 2021;Wen et al., 2024;Wen et al., 2022) but is supported by its connectivity with other regions such as the prefrontal cortex (PFC), insula, and hippocampus, which play critical roles in the evaluation, regulation, and contextualization of fear responses (Milad & Quirk, 2012; but see Fullana et al., 2019). Milad, Wright, et al. (2007) utilized fMRI to demonstrated that the ventromedial PFC is deactivated during fear acquisition but activated during fear extinction. ...
Interindividual differences in fear acquisition and extinction have been related to variation in specific brain correlates. However, variability in experimental setups complicates the integration of findings. Here, we present a combined fear acquisition (n = 101) and extinction (n = 88) experiment in which both phenomena were related to brain correlates obtained via functional magnetic resonance imaging in healthy, young participants. Correlates included regional brain volume, cortical surface area and thickness, neurite density and orientation dispersion, structural and functional connectivity. Fear responses were quantified as changes in skin conductance. Data from 376 brain areas and 70,500 network connections were used as independent variables in regularized regression models. Regression models of fear acquisition could be obtained for all modalities but regional brain volume. There were 284 predictors of which 77 appeared in exactly two models and 19 in exactly three. The latter primarily included brain areas from the somatosensory, insular, cingulate, and frontal cortices. Fear extinction yielded regression models based on neurite density, structural connectivity, and functional connectivity with 112 predictors in total. Two predictors, located in the dorsolateral prefrontal cortex, replicated across exactly two regression models (neurite density and structural connectivity). This study is the first to investigate the neural correlates of both fear acquisition and extinction in an explorative, multi-modal fMRI approach. Results show that numerous brain regions contribute to fear conditioning, some of them via more than one correlate. These findings call for further research to examine the potential interplay between brain correlates shaping fear conditioning.
... Research has shown that childhood trauma reduced functional connectivity between the amygdala and ventromedial prefrontal cortex [76]. The amygdala plays a central role in the fear conditioning circuit, while activation of the ventromedial prefrontal cortex is closely linked to fear extinction and the downregulation of amygdala-dependent fear responses [77]. This suggests that childhood trauma may contribute to emotional regulation failure and increase the risk of emotional disorders through its influence on the fear regulation circuit. ...
Background
Childhood trauma is strongly linked to anxiety and depression, significantly increasing the risk of negative outcomes in adulthood. This study employed network analysis to investigate the complex interplay of anxiety and depression symptoms among Chinese college students, focusing on identifying the core symptoms most directly affected by childhood trauma and those exerting the greatest influence on others.
Methods
Data were collected from December 2020 to January 2021 from 2,266 college students at 16 institutions in southwestern and eastern coastal China. Depression, anxiety, and childhood trauma were assessed using the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, and Childhood Trauma Questionnaire-28, respectively. Separate symptom networks were constructed for participants with and without childhood trauma experiences. Central indices were employed to identify the central symptom within each network. The accuracy and stability of the networks were then evaluated. Finally, a network comparison test was used to analyze differences in network properties between the trauma and non-trauma groups.
Results
Loss of Energy and Worry too much were the central symptoms in the non-trauma group, while anhedonia and nervousness were the central symptoms in the trauma group. There was a significant difference in the global strength of the network between the trauma group and the non-trauma group (pFDR< 0.01), but no significant difference in the distribution of edge weights between the two networks (pFDR =0.14). Anhedonia, Suicide ideation and Feeling afraid in the trauma group showed increased network centrality compared with the non-trauma group.
Conclusions
This study demonstrates the profound impact of childhood trauma on the central symptoms of anxiety and depression in college students. Further research is warranted to investigate the specific pathways through which these symptoms develop, with the goal of developing targeted interventions for this vulnerable population.
... This behavior requires both the suppression of cued freezing and movement toward a safe zone (Mowrer and Lamoreaux, 1946;Koolhaas et al., 1999;Moscarello and LeDoux, 2013;Moscarello and LeDoux, 2014;Krypotos et al., 2015;LeDoux et al., 2017). Active avoidance is similar to fear extinction in that cue-elicited freezing behavior mediated by the amygdala is suppressed during both behaviors (Phillips and LeDoux, 1992;Kim et al., 1993;Herry et al., 2010;Milad and Quirk, 2012;Moscarello and LeDoux, 2013;LeDoux et al., 2017). IL neural activity is higher in rats that successfully extinguish freezing to conditioned stimuli, and IL projects directly and indirectly to the central amygdala and is thought to suppress central amygdala outputs that mediate freezing (Milad and Quirk, 2002;Vertes, 2004;LeDoux et al., 2017). ...
The infralimbic cortex (IL) is essential for flexible behavioral responses to threatening environmental events. Reactive behaviors such as freezing or flight are adaptive in some contexts, but in others a strategic avoidance behavior may be more advantageous. IL has been implicated in avoidance, but the contribution of distinct IL neural subtypes with differing molecular identities and wiring patterns is poorly understood. Here, we study IL parvalbumin (PV) interneurons in mice as they engage in active avoidance behavior, a behavior in which mice must suppress freezing in order to move to safety. We find that activity in inhibitory PV neurons increases during movement to avoid the shock in this behavioral paradigm, and that PV activity during movement emerges after mice have experienced a single shock, prior to learning avoidance. PV neural activity does not change during movement toward cued rewards or during general locomotion in the open field, behavioral paradigms where freezing does not need to be suppressed to enable movement. Optogenetic suppression of PV neurons increases the duration of freezing and delays the onset of avoidance behavior, but does not affect movement toward rewards or general locomotion. These data provide evidence that IL PV neurons support strategic avoidance behavior by suppressing freezing.
... Extinction (or safety) learning is notably a core principle of exposure therapy that is leveraged to reduce maladaptive defensive responses (Craske et al., 2014(Craske et al., , 2022. Elucidating the mechanisms that modulate how conditioned defensive responses are acquired and extinguished thus holds high translational value across basic and clinical research, as well as clinical practice (Kredlow et al., 2018;Milad & Quirk, 2012;Zuj & Norrholm, 2019). ...
Pavlovian threat acquisition and extinction are fundamental processes by which individualslearn about threat and safety in their environment. Research has shown that humans learnmore rapidly and persistently to associate threatening and—somewhat counterintuitively—positive rewarding stimuli with aversive events, supporting predictions derived fromappraisal theories of emotion (Stussi et al., 2018; Stussi, Pourtois, et al., 2021). Here, thepresent study aimed to provide a confirmatory analysis of these findings and furthercharacterize their algorithmic bases. Data from the four original experiments (N = 247) usinga differential Pavlovian threat conditioning paradigm were combined and reanalyzed. In thisparadigm, threat-relevant (angry faces, snakes), positive-relevant (baby faces, happy faces,erotic images), and neutral (neutral faces, colored squares) stimuli were used as conditionedstimuli, and skin conductance response was measured as an index of learning. Computationalmodeling was applied to identify signatures of learning biases in Pavlovian threat acquisitionand extinction. An expanded model comparison indicated that a reinforcement-learningmodel differentiating between excitatory (learning from reinforcement) and inhibitory(learning from the absence of reinforcement) learning best explained the observed data.Although no evidence for differences in excitatory learning rates was found between stimuluscategories, both threat- and positive-relevant stimuli exhibited a lower inhibitory learning ratecompared to neutral stimuli, contributing to the persistence of the conditioned responseduring extinction. These results confirm the robustness of the original findings and furthervalidate the appraisal-based approach, thereby informing the affective and computationaldeterminants of Pavlovian threat extinction biases and their translational relevance.
... This process increases extinction neuron activity while decreasing fear neuron activity (Herry et al., 2008). This shift in neuronal activity is associated with a reduction in fear expression and an increase in approach behaviors towards the conditioned stimulus (Milad & Quirk, 2012). BLA neurons are also responsive to safety and reward stimuli. ...
The basolateral amygdala (BLA) is central to emotional processing, fear learning, and memory. Dopamine (DA) significantly influences BLA function, yet its precise effects are not clear. We present a mathematical model exploring how DA modulation of BLA activity depends on the network's current state. Specifically, we model the firing rates of interconnected neural groups in the BLA and their responses to external stimuli and DA modulation. BLA projection neurons are separated into two groups according to their responses—fear and safety. These groups are connected by mutual inhibition though interneurons. We contrast 'differentiated' BLA states, where fear and safety projection neurons exhibit distinct activity levels, with 'non-differentiated' states. We posit that differentiated states support selective responses and short-term emotional memory. On the other hand, non-differentiated states represent either the case in which BLA is disengaged, or the activation of the fear and safety neurons is at a similar moderate or high level. We show that, while DA further disengages BLA in the low activity state, it destabilizes the moderate activity non-differentiated BLA state. We show that in the latter non-differentiated state the BLA is hypersensitive, and the polarity of its responses (fear or safety) to salient stimuli is highly random. We hypothesize that this non-differentiated state is related to anxiety and Post-Traumatic Stress Disorder (PTSD).
... During fear acquisition, cues (conditioned stimuli or CS, e.g., coloured lights) presented on a computer screen are associated with an aversive outcome (e.g., electric shock). This is followed by the extinction learning phase where the CS is no longer paired with the aversive stimulus, resulting in the formation of a competing extinction memory trace, which inhibits the fear expression (Milad and Quirk 2012). After consolidating the fear and extinction memories, their respective strengths can be tested during extinction recall. ...
Post‐traumatic stress disorder (PTSD) is a highly debilitating condition that develops after trauma exposure. Dysregulation in extinction memory consolidation (i.e., the ability to remember that trauma‐related stimuli no longer signal danger) is proposed to underlie PTSD development. Disruptions in rapid eye movement (REM) sleep are thought to be the key contributor to this dysregulation, as REM sleep is suggested to play a vital role in the processing of emotional memories. While previous literature has investigated the role of natural REM sleep variations or REM sleep disruptions on extinction recall capacities, none have attempted to increase REM sleep to improve extinction recall. In this pilot, randomised controlled trial, we investigated the effect of 20 mg suvorexant to increase REM sleep, 20 mg temazepam to decrease REM sleep, and a placebo on extinction recall in 30 healthy adults (age: M = 26.93 years, SD = 7.54). Overall, no difference in REM percentage ( p = 0.68, η ² = 0.0.03, small effect), nor in extinction recall ( p = 0.58, η ² = 0.04, small effect) was observed between the drug conditions. However, increased REM percentage was associated with decreased conditioned fear response at recall, indicating better extinction recall ( β = −0.71, p = 0.03, η p ² = 0.10; moderate effect) across the sample. These findings suggest that increasing REM sleep in populations with REM disruptions such as PTSD to optimal levels could improve extinction recall. This underscores the potential of enhancing REM sleep as a therapeutic target for improving PTSD outcomes, warranting further investigation of suvorexant in clinical populations where REM sleep deficits are prevalent.
... Fear extinction learning, in which cues predicting an aversive event are presented repeatedly in the absence of threat to reduce emotional responding, is used as a preclinical animal model of exposure therapy [2][3][4]. The neuromodulator noradrenaline plays important roles in emotional learning as well as extinction [5][6][7][8][9][10] and dysfunction of noradrenergic signaling is observed in anxietyand stress-related disorders [11,12]. ...
Traumatic experiences produce powerful emotional memories which can subsequently be adaptively or pathologically modified through cognitive-evaluative mechanisms such as fear extinction learning. Noradrenaline from the brainstem locus coeruleus (LC) is activated during aversive emotion-inducing experiences, participates in extinction learning and is upregulated in individuals suffering from anxiety and trauma related disorders. The LC-noradrenaline system receives input from the medial prefrontal cortex (mPFC), a brain region important for cognitive and emotional control. However, it is unclear whether mPFC projections to LC regulate extinction and, if so, how distinct mPFC regions influence the LC to modulate emotional memories. Using viral based anatomical tracing techniques, we found that the LC receives topographically organized projections from the prelimbic (PL) and infralimbic (IL) subregions of mPFC in rats. Optogenetic inhibition approaches revealed that PL and IL inputs to LC inhibit or facilitate, respectively, the extinction of aversive memories. Moreover, LC-projecting neurons in PL and IL exhibit distinct activity patterns during extinction learning, with IL-to-LC neurons displaying sustained, sensory cue-evoked activation, while activity in PL-to-LC inputs is elevated during periods of externally and internally generated aversive emotional responding. Together, these results demonstrate that mPFC subregions opposingly regulate emotional memory extinction through their projections to the LC-noradrenaline system. These findings have important implications for understanding trauma related disorders which arise in part due to disrupted cognitive-emotional evaluations and impaired extinction.
... The second system, primarily involving cortical areas such as the lateral and medial prefrontal cortices, features the circuits through which conscious experiences emerge [46]. Studies indicate that the ventromedial prefrontal cortex (vmPFC) reduces amygdala activity (to inhibit fear expression and promote extinction), while the dorsal anterior cingulate (dACC) activates amygdala (to increase fear expression and oppose extinction) [47]. Furthermore, the dorsolateral prefrontal cortex (dlPFC) is involved in working memory and emotion regulation [48,49] and is a crucial region in the PTSD pathological circuitry [8]. ...
The amygdala has increasingly been proposed as a therapeutic target for patients with post-traumatic stress disorder (PTSD). However, the distinct contributions of the left and right amygdala to various aspects of fear processing remain inadequately understood. Here, we critically re-evaluate key findings from human functional neuroimaging and lesion studies on fear conditioning and extinction. We propose that while both amygdalae likely make critical contributions to fear processing, the right is more associated with sensory-mediated fear expression, and the left is associated with cognitive-mediated fear acquisition and extinction. With accumulating evidence from human lesion studies, we suggest that differentially targeting the right versus left amygdala for ablative or neuromodulatory therapies can be crucial for optimizing PTSD treatment.
... The BLA modulates anxiety and stress-associated behaviors, doing so partly through its regulation of the mPFC response to emotional stimuli. 32 The mPFC is the center for executive and cognitive functions and regulates the stress response at several system levels. It has been linked to maternal care as well as mood disorders such as PPD. ...
Background
Pregnancy affects learning and memory in women. Thus, to investigate the effects of pregnancy, the authors examined the brain electrophysiology of pregnant mice.
Methods
Using the whole‐cell patch‐clamp technique on isolated brain slices, we detected and compared the electrophysiological changes in the hippocampal CA1 (HIP CA1) region, medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) among 15 pregnant and 15 nonpregnant mice.
Results
In pregnant mice, there was a trend toward an increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs) (p = 0.092) and a trend toward a decrease in the amplitude of miniature inhibitory postsynaptic currents (mIPSC) (p = 0.071) in the HIP CA1. In the BLA, both the amplitudes of mEPSCs and mIPSCs were significantly reduced (p = 0.004 and 0.042, respectively). In the mPFC, the amplitudes of mEPSCs and hyperpolarization‐activated currents (Ih), as well as the frequencies of mIPSCs, were higher compared to nonpregnant mice (p = 0.035, 0.009, and 0.038, respectively).
Conclusions
In pregnant mice, the electrophysiological change in neurons in the mPFC and BLA might contribute to the cognitive and emotional changes during pregnancy. A trend toward electrophysiological change in the HIP CA1 revealed that the mechanism of cognitive change during pregnancy might differ from that of other conditions.
... Therefore, this article discusses the neural mechanisms associated with fear extinction. Previous studies of fear networks have primarily focused on the ventromedial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex, insular cortex, hippocampus, and amygdala (Milad and Quirk 2012;Picó-Pérez et al. 2019;Ressler 2020). The concept of a "fear extinction brain network" is primarily governed by the amygdala, hippocampus, and vmPFC (Gottfried and Dolan 2004;Hauner et al. 2013). ...
Non‐invasive brain stimulation (NIBS) is an emerging treatment for mental disorders that is painlessness and easy to administer. However, its effectiveness for modulating fear extinction requires further elucidation. We searched eight bibliographical databases and identified randomized controlled trials of NIBS and fear extinction in healthy populations. Outcomes were evaluated based on skin conductance responses (SCRs) under three experimental stimuli: threat condition stimulation (CS+), safe condition stimulation (CS−), and their discrimination (CS+ minus CS−). We applied a random‐effects model to determine effect sizes (Hedge's g) post‐stimulation and assessed article quality using Physiotherapy evidence database (PEDro) scale. Twenty‐one studies meeting systematic review criteria were included in this analysis, incorporating 40 independent effect sizes and data from 11 studies (n = 632) in the meta‐analysis. Compared with the control group, SCRs in CS+ and discrimination were significantly reducted in the intervention group. Fear extinction was more effective in the 24‐h test than immediately after NIBS. In conclusion, NIBS enhanced fear extinction, and the time interval between stimulation and testing may serve as a moderating variable.
... Exposure therapy is the state-of-art treatment approach for specific phobias (Chambless and Ollendick, 2001). The hypothesized mode of action for fear reduction in exposure therapy is extinction (Hamlett et al., 2023), a process that establishes an alternative non-fear memory to compete with and suppress the original fear memory (Milad and Quirk, 2012). As a consequence, the original memory trace of the fear-although no longer expressed-remains intact and can return over time, upon context renewal, or when the original fearful object or situation is unexpectedly encountered (Bouton, 2004(Bouton, , 1993Bouton and Bolles, 1979;Rescorla, 2004;Rescorla and Heth, 1975). ...
Return of fear after successful exposure therapy for phobia is a common clinical challenge. A previous study on mice demonstrated that the persistent attenuation of remote fear memories can be achieved by combining histone deacetylase inhibitors (HDACis) with fear-memory retrieval prior to extinction training. To evaluate the translational potential of this approach, we conducted a randomized, double-blind placebo-controlled trial. Forty-eight individuals with DSM-IV spider phobia received either HDACi valproic acid (VPA, 500 mg) or a placebo prior to the retrieval of fear memory followed by exposure therapy in virtual reality. No significant group difference was found in terms of behavioral change on the behavioral approach test at 3 months follow-up and baseline (primary outcome). However, the VPA group displayed significantly reduced fear in two self-report questionnaires related to spider phobia (Fear of Spider Questionnaire; Spider Phobia Beliefs Questionnaire) as compared to the placebo group. No group differences were observed for psychophysiological indicators of fear. The favorable impact of a single administration of VPA in combination with fear-memory retrieval prior to exposure therapy suggests that it might be an effective way to enhance symptom improvement at the subjective level in the treatment of phobias. Further studies need to investigate the conditions under which an improvement on the physiological and behavioral levels can be achieved as well.
... ACC activation also increased in pain overestimation conditions during emotion regulation. Therefore, Tsai et al. suggested that the ACC and amygdala integrate pain sensation and pain overestimation expectations during pain perception-which is congruent with the roles of the ACC and amygdala in anxiety and fear (Milad and Quirk, 2012). Additionally, during underestimation of pain, functional connectivity was detected between the medial orbitofrontal cortex (mOFC) and anterior hippocampus, with this functional connectivity strength correlating with the emotion model's predicted pain ratings in the pain underestimation condition. ...
... Of particular interest is the connectivity between the amygdalae and the left anterior cingulate cortex (ACC), emphasizing the involvement of the amygdalar nuclei in affective processing and emotional regulation. This functional co-occurrence contributes significantly to the detection of emotional responses and conflicts, and the integration of emotional signals with cognitive processes, contributing to adaptive emotional regulation and conflict resolution (Etkin et al. 2006;Milad and Quirk 2012). Anatomical evidence suggests that post-traumatic stress disorder (PTSD) may result from a disruption in fear extinction due to the interplay between the amygdala and left ACC (Rogers et al. 2009). ...
Co-activation of distinct brain areas provides a valuable measure of functional interaction, or connectivity, between them. One well-validated way to investigate the co-activation patterns of a precise area is meta-analytic connectivity modeling (MACM), which performs a seed-based meta-analysis on task-based functional magnetic resonance imaging (task-fMRI) data. While MACM stands as a powerful automated tool for constructing robust models of whole-brain human functional connectivity, its inherent limitation lies in its inability to capture the distinct interrelationships among multiple brain regions. Consequently, the connectivity patterns highlighted through MACM capture the direct relationship of the seed region with third brain regions, but also a (less informative) residual relationship between the third regions themselves. As a consequence of this, this technique does not allow to evaluate to what extent the observed connectivity pattern is really associated with the fact that the seed region is activated, or it just reflects spurious co-activations unrelated with it. In order to overcome this methodological gap, we introduce a meta-analytic Bayesian-based method, called meta-analytic connectivity perturbation analysis (MACPA), that allows to identify the unique contribution of a seed region in shaping whole-brain connectivity. We validate our method by analyzing one of the most complex and dynamic structures of the human brain, the amygdala, indicating that MACPA may be especially useful for delineating region-wise co-activation networks.
... Mice were trained in a classical, cued, delay fear conditioning paradigm (22,23). The conditioning phase consisted of eight pairings of a conditioned auditory stimulus (CS) lasting five seconds that was terminated by an unconditioned painful stimulus (US), consisting of a 500 ms footshock. ...
The prefrontal cortex (PFC) dopamine system plays an essential role in cognitive flexibility, working memory and psychiatric disease, but determining the conditions under which dopamine in the PFC is released remains an open problem. Both rewarding and aversive stimuli have been found to trigger release, but studies have disagreed on whether the valence of a stimulus or other variables like novelty and salience are the most important. Here we report on recordings of dopamine-dependent fluorescence using a high-sensitivity dopamine indicator. We deliver an array of rewarding, aversive and mixed valence stimuli, as well as stimuli without any obvious valence. We observe that stimuli without valence, as well as the omission of expected stimuli, do not lead to large changes in fluorescence, even when these stimuli and omissions are both novel and engaging. In contrast, both rewarding and aversive stimuli lead to increases in fluorescence, with the most rewarding and most aversive stimuli leading to the largest increases. We test the effect of adding an aversive component to a rewarding stimulus and find that the increases in fluorescence are consistent with a summation of the rewarding and aversive components. We propose that dopamine release in the PFC responds to the total valence of a stimulus, in contrast with the traditional view of basal ganglia dopamine release that depends on the net valence.
Major theories link variations in threat learning to the emergence of anxiety symptoms, especially during adolescence. Despite significant neural maturation of threat learning circuitry during this developmental stage, research on adolescence-specific neural responses during threat learning is limited. This study was the first to examine threat learning mechanisms through neural frequency activity among youth, focusing on activity in the theta (4–7 Hz) and alpha (8–12 Hz) frequency bands. Sixty-three adolescents and 65 adults completed a two-day threat acquisition and extinction procedure, while brain activity was measured using electroencephalography (EEG). Analyses focused on developmental differences in high temporal resolution changes in frequency activity, distinguishing between induced and evoked EEG signals. Developmental differences were mainly observed in frontal-central theta activity. During acquisition, adolescents showed higher induced theta activity to both threat and safety cues than adults. During extinction, adults showed decreased evoked theta activity to the conditioned stimulus, indicating effective inhibition of threat representations; in contrast, adolescents exhibited persistent threat contingencies throughout extinction. Both groups showed consistent alpha suppression towards the threat cue, suggesting sustained vigilance even during late extinction. Frontal-central theta activity is a valuable marker for capturing differences between adolescents and adults in threat learning. These findings add to mechanistic research efforts aiming to uncover factors contributing to anxiety vulnerability during adolescence.
A key function of brain systems mediating emotion is to learn to anticipate unpleasant experiences. Although organisms readily associate sensory stimuli with aversive outcomes, higher-order forms of emotional learning and memory require inference to extrapolate the circumstances surrounding directly experienced aversive events to other indirectly related sensory patterns that were not part of the original experience. This type of learning requires internal models of emotion, which flexibly track directly experienced and inferred aversive associations. Although the brain mechanisms of simple forms of aversive learning have been well studied in areas such as the amygdala1, 2, 3–4, whether and how the brain forms and represents internal models of emotionally relevant associations are not known⁵. Here we report that neurons in the rodent dorsomedial prefrontal cortex (dmPFC) encode a flexible internal model of emotion by linking sensory stimuli in the environment with aversive events, whether they were directly or indirectly associated with that experience. These representations form through a multi-step encoding mechanism involving recruitment and stabilization of dmPFC cells that support inference. Although dmPFC population activity encodes all salient associations, dmPFC neurons projecting to the amygdala specifically represent and are required to express inferred associations. Together, these findings reveal how internal models of emotion are encoded in the dmPFC to regulate subcortical systems for recall of inferred emotional memories.
The COVID-19 pandemic has resulted in persistent alterations in social cognition, trust, and behavior because of its long-term psychological and neurological effects. By conditioning individuals to associate proximity with risk, the pandemic-induced psychological distance has reshaped human interactions. This distance is enforced through social distancing and public health measures. Ultimately, this process has impacted societal cohesion, interpersonal relationships, and workplace behaviors by reinforcing avoidance behaviors, heightened social anxiety, and altering trust dynamics. An interdisciplinary approach that integrates neuroscience, psychology, and social science is necessary to comprehend these changes to address the challenges of re-establishing pre-pandemic norms.
Extinction learning is an important learning process that enables adaptive and flexible behavior. Human neuroimaging studies show that the neural basis of extinction learning consists of a neural network that includes the hippocampus, amygdala, and subcomponents of the prefrontal cortex, but also extends beyond them. The limitations of applying fMRI to actively participating animals have so far restricted the identification of the entire extinction network in non-human animals. Here, we present the first fMRI study of extinction in awake and actively participating pigeons, using a Go/NoGo operant paradigm with a water reward. Our study revealed an extensive and largely left hemispheric telencephalic network of sensory, limbic, executive, and motor areas that slowly ceased to be active during the process of extinction learning. We propose that the onset of extinction ignites a neuronal updating of the associated consequences of own actions within a large telencephalic neural network until a new association is established which inhibits the previously acquired operant response.
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.
Appetitive and aversive conditioning are both fundamental to adaptive behaviour, yet there remains limited understanding of how they differ on the behavioural and neural level. We investigated the two processes during acquisition and extinction using functional magnetic resonance imaging and behavioural measures. In a within-subject differential conditioning paradigm (preregistration DRKS00027448), aversive learning was induced by pairing visual cues with a temperature increase (pain rise), while appetitive learning involved a temperature decrease (pain reduction).
Valence and contingency ratings confirmed successful learning for both types of learning, though only the appetitive condition showed a return to baseline ratings during extinction, suggesting incomplete extinction in the aversive condition. On the neural level, both engaged the visual cortex during acquisition (with increased functional connectivity with the right frontal operculum) and the ventromedial prefrontal cortex (vmPFC) during extinction. However, aversive learning showed a stronger activation increase in the mediodorsal thalamus with heightened connectivity with the locus coeruleus during acquisition, as well as sustained parahippocampal activity during extinction. Moreover, incomplete extinction in the aversive condition (as indicated by contingency ratings) was associated with sustained activity in the visual cortex during pain anticipation.
These results suggest that while appetitive and aversive learning share activation in regions involved in sensory processing (occipital lobe) and learning (vmPFC), aversive learning uniquely engages areas promoting rapid acquisition (mediodorsal thalamus and locus coeruleus) and cautious unlearning, in line with the notion of a "better-safe-than-sorry" strategy.
Responding appropriately to potential threats before they materialize is critical to avoiding disastrous outcomes. Here we examine how threat-coping behavior is regulated by the tail of the striatum (TS) and its dopamine input. Mice were presented with a potential threat (a moving object) while pursuing rewards. Initially, the mice failed to obtain rewards but gradually improved in later trials. We found that dopamine in TS promoted avoidance of the threat, even at the expense of reward acquisition. Furthermore, the activity of dopamine D1 receptor-expressing neurons promoted threat avoidance and prediction. In contrast, D2 neurons suppressed threat avoidance and facilitated overcoming the potential threat. Dopamine axon activation in TS not only potentiated the responses of dopamine D1 receptor-expressing neurons to novel sensory stimuli but also boosted them acutely. These results demonstrate that an opponent interaction of D1 and D2 neurons in the TS, modulated by dopamine, dynamically regulates avoidance and overcoming potential threats.
Intense and chronic stress strengthens fear memories and increases the risk for mental disorders. Often stressful situations are experienced long before the appearance of the symptoms, but so far, little has been investigated on how distal stress alters fear memories. In a four-day paradigm, 131 healthy individuals were either assigned to the stress-group by means of the socially evaluated cold-pressor test (SECPT) or to the sham-group (control condition). Twenty-four hours later, participants underwent fear acquisition during which two shapes were presented. The first shape (conditioned stimulus, CS+) was associated with an electro-tactile stimulation (unconditioned stimulus, US), whereas the second shape (CS-) were presented alone. During extinction training, both shapes were presented while the US was omitted. To investigate if stress induction alters extinction recall differently depending on the passage of time, participants were tested either one day (recent) or 15 days (remote) after extinction training. Learning was quantified via subjective ratings, startle reflex and skin conductance response. While we found successful acquisition and extinction of the conditioned defensive responses, there was no effect of stress on these learning processes. Stress induction did not alter the spontaneous recovery of the conditioned defensive verbal responses but of the physiological responses as stressed individuals tested two weeks after extinction training showed startle potentiation to CS + vs. CS-. In conclusion, distal stress, even if mild, can strengthen fear memories and weaken extinction memory by the passage of time. This could be a possible mechanism facilitating the onset of stress-related and anxiety disorders.
In a world where AI is advancing faster than humanity’s ability to comprehend it, a new psychological phenomenon is emerging: DOHIAS (Depersonalization of Humanity AI Syndrome). Introduced by the author, DOHIAS describes a preference for AI interactions over human ones, driven by a fusion of four core fears: the fear of AI, the fear of humanity, the fear of the future, and the fear of love for humanity. Unlike other syndromes, DOHIAS reflects a shift in emotional allegiance from humans to machines. This paper explores its causes, symptoms, and potential treatment methods—including Cognitive Behavioral Therapy (CBT), Selective Serotonin Inhibitors (SSRIs), and exposure therapy using emotional AI algorithms. By integrating AI into therapeutic contexts, this paper proposes a path to manage DOHIAS before society fully hands over its social life to machines.
Parsing heterogeneity in the nature of adversity exposure and neurobiological functioning may facilitate better understanding of how adversity shapes individual variation in risk for and resilience against anxiety. One putative mechanism linking adversity exposure with anxiety is disrupted threat and safety learning. Here, we applied a person-centered approach (latent profile analysis) to characterize patterns of adversity exposure at specific developmental stages and threat/safety discrimination in corticolimbic circuitry in 120 young adults. We then compared how the resultant profiles differed in anxiety symptoms. Three latent profiles emerged: (1) a group with lower lifetime adversity, higher neural activation to threat, and lower neural activation to safety; (2) a group with moderate adversity during middle childhood and adolescence, lower neural activation to threat, and higher neural activation to safety; and (3) a group with higher lifetime adversity exposure and minimal neural activation to both threat and safety. Individuals in the second profile had lower anxiety than the other profiles. These findings demonstrate how variability in within-person combinations of adversity exposure and neural threat/safety discrimination can differentially relate to anxiety, and suggest that for some individuals, moderate adversity exposure during middle childhood and adolescence could be associated with processes that foster resilience to future anxiety.
Il disturbo da stress post-traumatico (Post Traumatic Stress Disorder, PTSD) è una condizione clinica che può interessare coloro che hanno subito un importante trauma psicologico ed è una delle principali cause di sofferenza psichica (Pagani, Cavallo, 2014). A livello globale si stima che la prevalenza del PTSD sia dell'11% tra le popolazioni colpite dai conflitti (APA, 2022). Le più attuali classificazioni nosografiche per l'inquadramento diagnostico dei disturbi dello spettro post-traumatico sono contenute nell'ultima revisione del manuale Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) (APA, 2022) e nell'International Classification of Diseases 11th Edition (ICD-11) (WHO, 2018). Il PTSD si presenta come un apprendimento disfunzionale che può portare a una risposta condizionata dalla paura elicitata da stimoli esterni o interni associati all'evento traumatico, che viene quindi richiamato alla memoria tramite dei flashback vividi e concomitanti reazioni involontarie associate a sentimenti negativi (Pagani et al., 2019). Studi di neuroimaging eseguiti su persone traumatizzate, sia bambini che adulti, hanno evidenziato alterazioni funzionali e anatomiche in diverse regioni cerebrali (Rinne-Albers et al., 2013; Siehl et al., 2018; Vyshka et al., 2023).
Posttraumatic stress disorder (PTSD) can be characterized as a disorder of fear learning and memory, in which there is a failure to retain memory for the extinction of conditioned fear. Sleep has been implicated in successful extinction retention. The coupling of sleep spindles to slow oscillations (SOs) during non-rapid eye movement sleep has been shown to broadly underpin the beneficial effect of sleep on memory consolidation. However, the role of this oscillatory coupling in the retention of extinction memories is unknown. In a large sample of 124 trauma-exposed individuals, we investigated SO-spindle coupling in relation to fear extinction memory. We found that participants with a PTSD diagnosis, relative to trauma-exposed controls, showed significantly altered SO-spindle timing, such that PTSD participants exhibited spindle coupling further away from the peak of the SO. Across participants, the amount of coupling significantly predicted extinction retention, with coupled spindles uniquely predicting successful extinction retention compared to uncoupled spindles. These results suggest that SO-spindle coupling is critical for successful retention of extinguished fear, and that SO-spindle coupling dynamics are altered in PTSD. These alterations in the mechanics of sleep may have substantial clinical implications, meriting further investigation.
Past results suggest that fear extinction and the return of extinguished fear are compromised in adolescents. However, findings have been inconclusive as there is a lack of fear extinction and extinction retention studies including children, adolescents and adults. In the present study, 36 children (6–9 years), 40 adolescents (13–17 years) and 44 adults (30–40 years), underwent a two-day fear conditioning task. Habituation, acquisition, and extinction were performed on the first day and an extinction retention test > 24 h later. Skin conductance responses were recorded during all phases of fear conditioning and functional magnetic resonance imaging (fMRI) was conducted during the fear retention test. All groups acquired and extinguished fear as measured with SCR, with no group differences in SCR during extinction retention. The groups had largely similar neural fear responses during the retention test, apart from adolescents displaying stronger amygdala fear response than children, with no differences between adolescents and adults. The findings do not support an adolescent extinction dip, and there was only marginal evidence of progressive changes in fear conditioning across development. In contrast to findings in rodents, fear conditioning in humans may elicit similar physiological responses and recruit similar neural networks from childhood to adulthood.
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.
Research on emotion regulation often focuses on cognitively effortful self-regulation strategies, but exposure to stress has been shown to interfere with the underlying mechanisms supporting such processes. Understanding alternative strategies that potentially bolster emotion regulation under stress is an important topic of investigation. Two potential alternatives involve everyday occurrences of social processing and memory recall. Social support and past emotional experiences may help in guiding us toward appropriate neurophysiological responses through overlapping circuitry with stress and reward systems, while also buttressing cognitive regulation strategies by expanding one’s perspective and allowing multiple opportunities to regulate retrospectively. In recognition that ongoing social and emotional events are often at the beginning of a cascade of both emotion regulation and memory processes, this chapter focuses on the emerging role of social relationships and autobiographical memory recall in regulating emotions under stress, highlighting opportunities and challenges associated with this process.
Religious beliefs can shape how people process fear. Yet the psychophysiological mechanisms underlying this phenomenon remain poorly understood. We investigated fear learning and extinction processes in a group of individuals who professed a belief in God, compared to non-believers. Using a virtual reality Pavlovian fear conditioning/extinction task, we measured neurovegetative activity associated with these forms of associative learning. Our finding shows reduced fear extinction among God believers, compared to non-believers. This suggests that the general mechanism of fear extinction learning is suppressed in these individuals. Importantly, this effect was not explained by state or trait anxiety scores. These findings align with previous evidence linking religiosity and spirituality with the neural circuit of fear and suggest that religiosity may be associated with weaker inhibitory learning processes related to fear.
Pavlovian eyeblink (EB) conditioning was studied in both trace and delay paradigms in rabbits (Oryctolagus cuniculus) with either medial prefrontal cortex (mPFC) lesions or sham lesions. mPFC lesions of prelimbic cortex (Brodmann's Area 32) retarded EB conditioning in the trace but not the delay paradigm. However, this effect was significant only when the conditioned stimulus (CS) was 500 rather than 100 ms in duration. Lesions of the anterior cingulate cortex (Area 24) did not affect EB conditioning in a trace paradigm. Accompanying CS-evoked heart rate slowing was attenuated under all conditions by the mPFC lesions, although this result was not always statistically significant.
In Experiment 1 four groups of rats received 30 light-shock pairings using footshock intensities of either .2, .4, .8, or 1.6 mA. One day later all rats were tested for startle by presenting tones in the presence or absence of the light CS. Potentiated startle (the difference between startle on light-tone vs tone-alone trials) was nonmonotonically related to the shock intensity used in training, with the greatest potentiation at intermediate shock levels. Experiment 3 demonstrated a similar relationship when backshocks instead of footshocks were used. In Experiment 2 rats were trained with either a moderate or high shock and then given an extended extinction-test session 1 day later. The moderate-shock group showed a gradual decline in potentiated startle over extinction. The high-shock group showed a nonmonotonic extinction curve where potentiation progressively increased toward the middle of extinction and dissipated thereafter. The results suggest that acoustic startle bears an inverted U-shaped relationship to fear and are discussed in relation to other studies concerned with this issue.
In this article I review research and theory on the "interference paradigms" in Pavlovian learning. In these situations (e.g., extinction, counterconditioning, and latent inhibition), a conditioned stimulus (CS) is associated with different unconditioned stimuli (USs) or outcomes in different phases of the experiment; retroactive interference, proactive interference, or both are often observed. In all of the paradigms, contextual stimuli influence performance, and when information is available, so does the passage of time. Memories of both phases are retained, and performance may depend on which is retrieved. Despite the similarity of the paradigms, conditioning theories tend to explain them with separate mechanisms. They also do not provide an adequate account of the context's role, fail to predict the effects of time, and overemphasize the role of learning or storage deficits. By accepting 4 propositions about animal memory (i.e., contextual stimuli guide retrieval, time is a context, different memories are differentially dependent on context, and interference occurs at performance output), a memory retrieval framework can provide an integrated account of context, time, and performance in the various paradigms.
Individual differences in a person's ability to control fear have been linked to activation in the dorsal anterior cingulate cortex, the ventromedial prefrontal cortex, and the amygdala. This study investigated whether functional variance in this network can be predicted by resting metabolism in these same regions.
The authors measured resting brain metabolism in healthy volunteers with positron emission tomography using [18F]fluorodeoxyglucose. This was followed by a 2-day fear conditioning and extinction training paradigm using functional MRI to measure brain activation during fear extinction and recall. The authors used skin conductance response to index conditioned responding, and they used resting metabolism in the amygdala, the dorsal anterior cingulate cortex, and the ventromedial prefrontal cortex to predict responses during fear extinction and extinction recall.
During extinction training, resting amygdala metabolism positively predicted activation in the ventromedial prefrontal cortex and negatively predicted activation in the dorsal anterior cingulate cortex. In contrast, during extinction recall, resting amygdala metabolism negatively predicted activation in the ventromedial prefrontal cortex and positively predicted activation in the dorsal anterior cingulate cortex. In addition, resting metabolism in the dorsal anterior cingulate cortex predicted fear expression (as measured by skin conductance response) during extinction recall.
Resting brain metabolism predicted neuronal reactivity and skin conductance changes associated with the recall of the fear extinction memory.
Men and women differ in their ability to extinguish fear. Fear extinction requires the activation of brain regions, including the ventromedial prefrontal cortex (vmPFC) and amygdala. Could estradiol modulate the activity of these brain regions during fear extinction?
All rat experiments were conducted in naturally cycling females. Rats underwent fear conditioning on Day 1. On Day 2, they underwent extinction training during the metestrus phase of the cycle (low estrogen and progesterone). Extinction recall was assessed on Day 3. Systemic injections of estrogen receptor-beta and -alpha agonists and of estradiol were administered at different time points to assess their influence on extinction consolidation and c-Fos expression in the vmPFC and amygdala. In parallel, healthy naturally cycling women underwent an analogous fear conditioning extinction training in a 3T functional magnetic resonance scanner. Measurement of their estradiol levels and skin conductance responses were obtained throughout the experiment.
In female rats, administration of the estrogen-receptor beta (but not alpha) agonist facilitated extinction recall. Immediate (but not delayed) postextinction training administration of estradiol facilitated extinction memory consolidation and increased c-Fos expression in the vmPFC while reducing it in the amygdala. In parallel, natural variance in estradiol in premenopausal cycling women modulated vmPFC and amygdala reactivity and facilitated extinction recall.
We provide translational evidence that demonstrates the influence of endogenous and exogenous estradiol on the fear extinction network. Our data suggest that women's endogenous hormonal status should be considered in future neurobiological research related to anxiety and mood disorders.
It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory.
Anxiety--a sustained state of heightened apprehension in the absence of immediate threat--becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)--achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA--exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA-CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.
Acute stress exposure enhances classical eyeblink conditioning in male rats, whereas exposure to the same event dramatically impairs performance in females (Wood and Shors, 1998; Wood et al., 2001). We hypothesized that stress affects learning differently in males and females because different brain regions and circuits are being activated. In the first experiment, we determined that neuronal activity within the medial prefrontal cortex (mPFC) during the stressful event is necessary to disrupt learning in females. In both males and females, the mPFC was bilaterally inactivated with GABA agonist muscimol before the stressor. Inactivation prevented only the impaired performance in females; it had no consequence for performance in males. However, in the second experiment, excitation of the mPFC alone with GABA antagonist picrotoxin was insufficient to elicit the stress effect that was prevented through the inactivation of this region in females. Therefore, we hypothesized that the mPFC communicates with the basolateral amygdala to disrupt learning in females after the stressor. To test this hypothesis, these structures were disconnected from each other with unilateral excitotoxic (NMDA) lesions on either the same or opposite sides of the brain. Females with contralateral lesions, which disrupt the connections on both sides of the brain, were able to learn after the stressful event, whereas those with ipsilateral lesions, which disrupt only one connection, did not learn after the stressor. Together, these data indicate that the mPFC is critically involved in females during stress to impair subsequent learning and does so via communication with the amygdala.
Despite increasing awareness of the many important roles played by brain-derived neurotrophic factor (BDNF) activation of TrkB, a fuller understanding of this system and the use of potential TrkB-acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB receptors in vivo. However, 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intraperitoneal administration. The authors combined pharmacological, biochemical, and behavioral approaches in a preclinical study examining the role of 7,8-DHF in modulating emotional memory in mice.
The authors first examined the ability of systemic 7,8-DHF to activate TrkB receptors in the amygdala. They then examined the effects of systemic 7,8-DHF on acquisition and extinction of conditioned fear, using specific and well-characterized BDNF-dependent learning paradigms in several models using naive mice and mice with prior traumatic stress exposure.
Amygdala TrkB receptors, which have previously been shown to be required for emotional learning, were activated by systemic 7,8-DHF (at 5 mg/kg i.p.). 7,8-DHF enhanced both the acquisition of fear and its extinction. It also appeared to rescue an extinction deficit in mice with a history of immobilization stress.
These data suggest that 7,8-DHF may be an excellent agent for use in understanding the effects of TrkB activation in learning and memory paradigms and may be attractive for use in reversing learning and extinction deficits associated with psychopathology.
Cognitive behavioral therapy (CBT) represents a learning process leading to symptom relief and resulting in long-term changes in behavior. CBT for panic disorder is based on exposure and exposure-based processes can be studied in the laboratory as extinction of experimentally acquired fear responses. We have recently demonstrated that the ability to extinguish learned fear responses is associated with a functional genetic polymorphism (COMTval158met) in the COMT gene and this study was aimed at transferring the experimental results on the COMTval158met polymorphism on extinction into a clinical setting.
We tested a possible effect of the COMTval158met polymorphism on the efficacy of CBT, in particular exposure-based treatment modules, in a sample of 69 panic disorder patients.
We present evidence that panic patients with the COMTval158met met/met genotype may profit less from (exposure-based) CBT treatment methods as compared to patients carrying at least one val-allele. No association was found with the 5-HTTLPR/rs25531 genotypes which is presented as additional material.
We were thus able to transfer findings on the effect of the COMTval158met polymorphism from an experimental extinction study obtained using healthy subjects to a clinical setting. Furthermore patients carrying a COMT val-allele tend to report more anxiety and more depression symptoms as compared to those with the met/met genotype. Limitations of the study as well as possible clinical implications are discussed.
Clinical Trial Registry name: Internet-Versus Group-Administered Cognitive Behavior Therapy for Panic Disorder (IP2). Registration Identification number: NCT00845260, http://www.clinicaltrials.gov/ct2/show/NCT00845260.
The central amygdala (CEA), a nucleus predominantly composed of GABAergic inhibitory neurons, is essential for fear conditioning. How the acquisition and expression of conditioned fear are encoded within CEA inhibitory circuits is not understood. Using in vivo electrophysiological, optogenetic and pharmacological approaches in mice, we show that neuronal activity in the lateral subdivision of the central amygdala (CEl) is required for fear acquisition, whereas conditioned fear responses are driven by output neurons in the medial subdivision (CEm). Functional circuit analysis revealed that inhibitory CEA microcircuits are highly organized and that cell-type-specific plasticity of phasic and tonic activity in the CEl to CEm pathway may gate fear expression and regulate fear generalization. Our results define the functional architecture of CEA microcircuits and their role in the acquisition and regulation of conditioned fear behaviour.
Activation of the infralimbic region (IL) of the medial prefrontal cortex (mPFC) reduces conditioned fear in a variety of situations, and the IL is thought to play an important role in the extinction of conditioned fear. Here we report a series of experiments using contextual fear conditioning in which the IL is activated with the GABAa antagonist picrotoxin (Ptx) during a single extinction session in the fear context. We investigate the impact of this manipulation on subsequent extinction sessions in which Ptx is no longer present. First, we demonstrate that a single treatment with intra-IL Ptx administered in a conditioned fear context greatly accelerates the rate of extinction on the following days. Importantly, IL-Ptx also enhances extinction to a different fear context than the one in which IL-Ptx was administered. Thus, IL-Ptx primes extinction learning regardless of the fear context in which the IL was initially activated. Second, activation of the IL must occur in conjunction with a fear context in order to enhance extinction; the extinction enhancing effect is not observable if IL-Ptx is administered in a neutral context. Finally, this extinction enhancing effect is specific to the IL for it does not occur if Ptx is injected into the prelimbic region (PL) of the mPFC. The results indicate a novel persisting control of fear induced by activation of the IL and suggest that IL activation induces changes in extinction-related circuitry that prime extinction learning.
Synaptically released Zn²+ is a potential modulator of neurotransmission and synaptic plasticity in fear-conditioning pathways. Zinc transporter 3 (ZnT3) knock-out (KO) mice are well suited to test the role of zinc in learned fear, because ZnT3 is colocalized with synaptic zinc, responsible for its transport to synaptic vesicles, highly enriched in the amygdala-associated neural circuitry, and ZnT3 KO mice lack Zn²+ in synaptic vesicles. However, earlier work reported no deficiency in fear memory in ZnT3 KO mice, which is surprising based on the effects of Zn²+ on amygdala synaptic plasticity. We therefore reexamined ZnT3 KO mice in various tasks for learned and innate fear. The mutants were deficient in a weak fear-conditioning protocol using single tone-shock pairing but showed normal memory when a stronger, five-pairing protocol was used. ZnT3 KO mice were deficient in memory when a tone was presented as complex auditory information in a discontinuous fashion. Moreover, ZnT3 KO mice showed abnormality in trace fear conditioning and in fear extinction. By contrast, ZnT3 KO mice had normal anxiety. Thus, ZnT3 is involved in associative fear memory and extinction, but not in innate fear, consistent with the role of synaptic zinc in amygdala synaptic plasticity.
The amygdala is a central component of the limbic brain system and is known to be vital to understanding aspects of emotion, memory and social behaviour. Dysfunction of the structure is also thought to contribute to a variety of disorders, including autism, Alzheimer's Disease and schizophrenia. The nature of its contribution to these fundamental aspects of behaviour and cognition, and its relationship with other regions of the brain has remained elusive. However, since Aggleton's first book on the subject - The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction (1992) - there have been major advances in our understanding of the processes involved and a dramatic rise in the volume of research. Scientists are now able to define its contribution in an increasingly precise manner. Leading experts from around the world have contributed chapters to this comprehensive and unique review, describing current thinking on this enigmatic brain structure. This is a book for all those with an interest in the neural basis of emotion and memory.
10.1111/j.1460-9568.2010.07101.x
Objective: The purpose of this study was to determine whether anterior limbic and paralimbic regions of the brain are differentially activated during the recollection and imagery of traumatic events in trauma-exposed individuals with and without posttraumatic stress disorder (PTSD). Method: Positron emission tomography (PET) was used to measure normalized regional cerebral blood flow (CBF) in 16 women with histories of childhood sexual abuse: eight with current PTSD and eight without current PTSD. In separate script-driven imagery conditions, participants recalled and imagined traumatic and neutral autobiographical events. Psychophysiologic responses and subjective ratings of emotional state were measured for each condition. Results: In the traumatic condition versus the neutral control conditions, both groups exhibited regional CBF increases in orbitofrontal cortex and anterior temporal poles; however, these increases were greater in the PTSD group than in the comparison group. The comparison group exhibited regional CBF increases in insular cortex and anterior cingulate gyrus; increases in anterior cingulate gyrus were greater in the comparison group than in the PTSD group. Regional CBF decreases in bilateral anterior frontal regions were greater in the PTSD group than in the comparison group, and only the PTSD group exhibited regional CBF decreases in left inferior frontal gyrus. Conclusions: The recollection and imagery of traumatic events versus neutral events was accompanied by regional CBF increases in anterior paralimbic regions of the brain in trauma-exposed individuals with and without PTSD. However, the PTSD group had greater increases in orbitofrontal cortex and anterior temporal pole, whereas the comparison group had greater increases in anterior cingulate gyrus.
Four conditioned suppression experiments examined the influence of contextual stimuli on the rat's fear of an extinguished conditioned stimulus (CS). When rats received pairings of a CS with shock in one context and then extinction of the CS in another context, fear of the CS was renewed when the CS was returned to and tested in the original context (Experiments 1 and 3). No such renewal was obtained when the CS was tested in a second context after extinction had occurred in the conditioning context (Experiment 4). In Experiment 2, shocks presented following extinction reinstated fear of the CS, but only if they were presented in the context in which the CS was tested. In each experiment, the associative properties of the contexts were independently assessed. Contextual excitation was assessed primarily with context-preference tests in which the rats chose to sit in either the target context or an adjoining side compartment. Contextual inhibition was assessed with summation tests. Although reinstatement was correlated with demonstrable contextual excitation present during testing, the renewal effect was not. Moreover, there was no evidence that contextual inhibition developed during extinction. The results suggest that fear of an extinguished CS can be affected by the excitatory strength of the context but that independently demonstrable contextual excitation or inhibition is not necessary for contexts to control that fear.
The authors investigated the role of medial prefrontal cortex (mPFC) in the inhibition of conditioned fear in rats using both Pavlovian extinction and conditioned inhibition paradigms. In Experiment 1, lesions of ventral mPFC did not interfere with conditioned inhibition of the fear-potentiated startle response. In Experiment 2, lesions made after acquisition of fear conditioning did not retard extinction of fear to a visual conditioned stimulus (CS) and did not impair "reinstatement" of fear after unsignaled presentations of the unconditioned stimulus. In Experiment 3, lesions made before fear conditioning did not retard extinction of fear-potentiated startle or freezing to an auditory CS. In both Experiments 2 and 3, extinction of fear to contextual cues was also unaffected by the lesions. These results indicate that ventral mPFC is not essential for the inhibition of fear under a variety of circumstances.
Ontogenetic development of active avoidance learning, extinction and retention was studied in rats. The learning of a 1-way active avoidance was most rapid between Weeks 4 and 6, although some slight gender-related differences were evident. No such unambiguous development was detected in forced extinction. The 24-hr retention of avoidance peaked at the age of 4 weeks whereas 1-month retention was best in animals trained at the age of 8 weeks. The retrieval of memory trace also had best values at these ages. Retention of forced extinction was found to peak in 6-week animals. The existence of developmental “critical periods” must be considered cautiously as various functions have different time courses depending upon the chosen parameters in assessment.
Discrete lesion of the genual portion of the anterior cingulate gyrus in three dogs produced temporary disinhibition of preoperatively
trained inhibitory food conditioned responses. This disinhibition was accompanied by increase in general behavior motivated
by food reinforcement. Lesion of the posterior cingulate gyrus in three other dogs did not produce such impairment.
Acquisition and extinction of fear responses conditioned to a visual stimulus were examined in rats with ablations of visual cortex. Visual cortex lesions did not interfere with acquisition, indicating that visual fear conditioning, like auditory fear conditioning, is mediated by sub-cortical, probably thalamo-amygdala, sensory pathways. In contrast to acquisition, extinction was greatly prolonged, if not prevented, by cortical ablation. This resistance to extinction of sub cortical emotional memories may explain certain aspects of emotional memory in man.
Argues that neither the psychodynamic nor the conditioned response (CR) theory is sufficient to explain the persistence of posttraumatic stress disorder (PTSD). Although the traumatic event (e.g., warfare, natural disaster) can be seen as a unconditioned stimulus/stimuli (UCS), spontaneous flashbacks do not fit well with the notion of stimulus generalization. PTSD has also been shown to develop in previously mentally healthy persons. Emotional network theory, as proposed by P. J. Lang (1985), is illustrated in a recollection of a combat experience, wherein certain propositions act as emotional stimuli from memory to be connected with emotional response and meaning propositions. Assessment, prevention, and treatment are discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The startle response in rats to a sudden sound was increased when the startle was elicited in the presence of a flashing light (CS) which had previously been paired with electric shock. The magnitude of this potentiated startle was used as a measure of the conditioned fear elicited by the CS.
The effects of different doses of amobarbital sodium on the potentiated startle, the startle in the presence of a flashing light which had not been paired with shock, and the startle to electric shock were tested. It was found that the drug reduced the magnitude of the potentiated startle response and reduced even more the startle to electric shock, but apparently had little, if any, effect on the startle to loud sound in the presence of a neutral CS. The effects lasted for at least 90 min after i.p. injections of the drug.
The action of amobarbital was interpreted in terms of a selective reduction in the strength of the fear drive, but other interpretations were not ruled out.
The fact that this drug produced differential effects on startle responses elicited in different ways, suggests that such responses may be useful measures of differential psychopharmacological effects.
EEG changes induced by intraperitoneal injection of 6 mg/kg atropine sulphate were studied in freely moving rats with implanted
electrodes. Sleep-like high voltage slow wave activity appeared in neocortex, hippocampus and reticular formation attaining
maximum approximately 20 minutes after atropine injection. At the height of the atropine effect one-trial learning of a passive
avoidance reaction was partly impaired. So was extinction of this overtrained reaction. Atropine injected 20 minutes before
the retention test adversely affected retrieval of threshold conditioned reactions; this effect could not be demonstrated
with slightly overtrained behavior. Atropine impaired neither the consolidation nor the storage of memory traces. The atropine
induced dissociation between EEG and behavior is discussed.
The prefrontal cortex (PFC) mediates a range of higher order ‘executive functions’ that subserve the selection and processing of information in such a way that behavior can be planned, controlled and directed according to shifting environmental demands. Impairment of executive functions typifies many forms of psychopathology, including schizophrenia, mood and anxiety disorders and addiction, that are often associated with a history of trauma and stress. Recent research in animal models demonstrates that exposure to even brief periods of intense stress is sufficient to cause significant structural remodeling of the principle projection neurons within the rodent PFC. In parallel, there is growing evidence that stress-induced alterations in PFC neuronal morphology are associated with deficits in rodent executive functions such as working memory, attentional set-shifting and cognitive flexibility, as well as emotional dysregulation in the form of impaired fear extinction. Although the molecular basis of stress-induced changes in PFC morphology and function are only now being elucidated, an understanding of these mechanisms could provide important insight into the pathophysiology of executive dysfunction in neuropsychiatric disease and foster improved strategies for treatment.
The present study was designed as an initial step in determining the specific anatomical systems of the amygdala which may contribute to the expression of conditioned heart rate responding during aversive Pavlovian conditioning in the New Zealand rabbit. Animals receiving either small or large radio-frequency lesions of the central nucleus of the amygdala demonstrated a significant attenuation of the conditioned bradycardia response to the conditioned stimulus when compared to that demonstrated by control animals. No significant effects of the lesions on baseline heart rate or on the heart rate orienting response to the conditioned stimulus were observed. Central nucleus lesions also produced a significant effect on the unconditioned heart rate response to the unconditioned stimulus manifested in an increased duration and prolonged habituation of the unconditioned response. The results are consistent with anatomical and physiological evidence suggesting the involvement of the central nucleus in the expression of emotional responses including accompanying cardiovascular alterations.
Rationale:
Systemic administration of cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa, is able to attenuate cardiovascular and behavioral (freezing) changes induced by re-exposure to a context that had been previously paired with footshocks. The brain sites mediating this effect, however, remain unknown. The medial prefrontal cortex (mPFC) has been related to contextual fear conditioning.
Objectives:
(1) To verify, using c-Fos immunocytochemistry, if the mPFC is involved in the attenuation of contextual fear induced by systemic administration of CBD; (2) to investigate if direct microinjections of CBD into mPFC regions would also attenuate contextual fear.
Results:
Confirming previous results systemic administration of CBD (10mg/kg) decreased contextual fear and associated c-Fos expression in the prefrontal cortex (prelimbic and infralimbic regions). The drug also attenuated c-Fos expression in the bed nucleus of the stria terminalis (BNST). Direct CBD (30 nmol) microinjection into the PL prefrontal cortex reduced freezing induced by re-exposure to the aversively conditioned context. In the infralimbic (IL) prefrontal cortex, however, CBD (30 nmol) produced an opposite result, increasing the expression of contextual fear conditioning. This result was confirmed by an additional experiment where the conditioning session was performed under a less aversive protocol.
Conclusion:
These results suggest that the PL prefrontal cortex may be involved in the attenuation of contextual fear induced by systemic injection of CBD. They also support the proposition that the IL and PL play opposite roles in fear conditioning. A possible involvement of the BNST in CBD effects needs to be further investigated.
The behavior of rats during the acquisition and extinction of a brightness discrimination was altered by bilateral hippocampal lesions. Lesions restricted to the neopallium overlying the hippocampus did not significantly affect behavior. While brain damage did not increase the number of trials required to reach the acquisition criterion, rats with hippocampal lesions did generate significantly longer position hypotheses during acquisition. During extinction, rats with hippocampal damage showed no increase in approach response latency and made significantly longer brightness, but not position hypotheses. These results, together with previous findings, strengthen the conclusion that the behavior of rats in low ratio reinforcement situations is particularly sensitive to the disruptive effects of hippocampal damage. Such damage may produce behavioral effects by altering the brain processes necessary for the shifts of attention which can be inferred to occur in normal animals in such situations.
Four monkeys with orbital frontal lesions, four with lateral frontal lesions, and four unoperated controls, all of which had been trained preoperatively to press a lever for food reward, were tested in conditioning sessions alternating with extinction sessions. One month later, similar conditioning and extinction tests were carried out under conditions of food deprivation and satiation. Compared to either of the other two groups, the orbital frontal animals gave more responses in extinction and showed a smaller response decrement in conditioning sessions when shifted from deprivation to satiation. These findings support the view advanced in an earlier study that the orbital frontal monkey's impairment on stimulus differentiation tests is due to a difficulty in withholding responses on negative trials. Although previous studies suggest a similar impairment in lateral frontal monkeys, the procedures used in the present experiment failed to detect it.
Resting-state functional connectivity magnetic resonance imaging (fcMRI) studies constitute a growing proportion of functional brain imaging publications. This approach detects temporal correlations in spontaneous blood oxygen level-dependent (BOLD) signal oscillations while subjects rest quietly in the scanner. Although distinct resting-state networks related to vision, language, executive processing, and other sensory and cognitive domains have been identified, considerable skepticism remains as to whether resting-state functional connectivity maps reflect neural connectivity or simply track BOLD signal correlations driven by nonneural artifact. Here we combine diffusion tensor imaging (DTI) tractography with resting-state fcMRI to test the hypothesis that resting-state functional connectivity reflects structural connectivity. These 2 modalities were used to investigate connectivity within the default mode network, a set of brain regions--including medial prefrontal cortex (MPFC), medial temporal lobes (MTLs), and posterior cingulate cortex (PCC)/retropslenial cortex (RSC)--implicated in episodic memory processing. Using seed regions from the functional connectivity maps, the DTI analysis revealed robust structural connections between the MTLs and the retrosplenial cortex whereas tracts from the MPFC contacted the PCC (just rostral to the RSC). The results demonstrate that resting-state functional connectivity reflects structural connectivity and that combining modalities can enrich our understanding of these canonical brain networks.
We investigated whether resting brain metabolism can be used to predict autonomic and neuronal responses during fear conditioning in 20 healthy humans. Regional cerebral metabolic rate for glucose was measured via positron emission tomography at rest. During conditioning, autonomic responses were measured via skin conductance, and blood oxygen level dependent signal was measured via functional magnetic resonance imaging. Resting dorsal anterior cingulate metabolism positively predicted differentially conditioned skin conductance responses. Midbrain and insula resting metabolism negatively predicted midbrain and insula functional reactivity, while dorsal anterior cingulate resting metabolism positively predicted midbrain functional reactivity. We conclude that resting metabolism in limbic areas can predict some aspects of psychophysiological and neuronal reactivity during fear learning.
This review highlights progress over the past decade in research on the effects of mass trauma experiences on children and youth, focusing on natural disasters, war, and terrorism. Conceptual advances are reviewed in terms of prevailing risk and resilience frameworks that guide basic and translational research. Recent evidence on common components of these models is evaluated, including dose effects, mediators and moderators, and the individual or contextual differences that predict risk or resilience. New research horizons with profound implications for health and well-being are discussed, particularly in relation to plausible models for biological embedding of extreme stress. Strong consistencies are noted in this literature, suggesting guidelines for disaster preparedness and response. At the same time, there is a notable shortage of evidence on effective interventions for child and youth victims. Practical and theory-informative research on strategies to protect children and youth victims and promote their resilience is a global priority.
In this review, the authors propose that the fear extinction model can be used as an experimental tool to cut across symptom dimensions of multiple anxiety disorders to enhance our understanding of the psychopathology of these disorders and potentially facilitate the detection of biomarkers for them. The authors evaluate evidence for this proposition from studies examining the neurocircuitry underlying fear extinction in rodents, healthy humans, and clinical populations. The authors also assess the potential use of the fear extinction model to predict vulnerability for anxiety and treatment response and to improve existing treatments or develop novel ones. Finally, the authors suggest potential directions for future research that will help to further validate extinction as a biomarker for anxiety across diagnostic categories and to bridge the gap between basic neuroscience and clinical practice.
Resting-state functional connectivity (RSFC) measured by functional magnetic resonance imaging has played an essential role in understanding neural circuitry and brain diseases. The vast majority of RSFC studies have been focused on positive RSFC, whereas our understanding about its conceptual counterpart - negative RSFC (i.e. anticorrelation) - remains elusive. To date, anticorrelated RSFC has yet been observed without the commonly used preprocessing step of global signal correction. However, this step can induce artifactual anticorrelation (Murphy et al., 2009), making it difficult to determine whether the observed anticorrelation in humans is a processing artifact (Fox et al., 2005). In this report we demonstrated robust anticorrelated RSFC in a well characterized frontolimbic circuit between the infralimbic cortex (IL) and amygdala in the awake rat. This anticorrelation was anatomically specific, highly reproducible and independent of preprocessing methods. Interestingly, this anticorrelated relationship was absent in anesthetized rats even with global signal correction, further supporting its functional significance. Establishing negative RSFC independent of data preprocessing methods will significantly enhance the applicability of RSFC in better understanding neural circuitries and brain networks. In addition, combining the neurobiological data of the IL-amygdala circuit in rodents, the finding of the present study will enable further investigation of the neurobiological basis underlying anticorrelation.
Research during the past decade has led to a tremendous growth in our understanding of how fear memories are acquired and subsequently inhibited on a neural and molecular level. Such research has contributed to significant developments in the treatment of anxiety disorders, and has considerably advanced our understanding of the neurobiology of learning and memory in general. A number of recent studies have examined the role of growth factors in the formation of long-term memory for fearful events, due to their ability to cause morphological neural changes in response to environmental stimulation. In this review we first describe physiological evidence that fibroblast growth factor-2 (FGF2) receptors are highly expressed in the neural circuitry regulating fear acquisition and extinction, and that FGF2 modulates the molecular signals known to be involved in the formation of fear memories. Then we present emerging behavioral research that demonstrates that exogenous FGF2 can enhance the formation of fear conditioning and extinction memories. Finally, we briefly discuss how research into the role of FGF2 in learning and memory may be of clinical benefit, particularly in the treatment of anxiety disorders.
The dynamic interactions between the amygdala and the medial prefrontal cortex (mPFC) are usefully conceptualized as a circuit that both allows us to react automatically to biologically relevant predictive stimuli as well as regulate these reactions when the situation calls for it. In this review, we will begin by discussing the role of this amygdala-mPFC circuitry in the conditioning and extinction of aversive learning in animals. We will then relate these data to emotional regulation paradigms in humans. Finally, we will consider how these processes are compromised in normal and pathological anxiety. We conclude that the capacity for efficient crosstalk between the amygdala and the mPFC, which is represented as the strength of the amygdala-mPFC circuitry, is crucial to beneficial outcomes in terms of reported anxiety.
Cognitive flexibility is critical for survival and reflects the malleability of the central nervous system (CNS) in response to changing environmental demands. Normal aging results in difficulties modifying established behaviors, which may involve medial prefrontal cortex (mPFC) dysfunction. Using extinction of conditioned fear in rats to assay cognitive flexibility, we demonstrate that extinction deficits reminiscent of mPFC dysfunction first appear during middle age, in the absence of hippocampus-dependent context deficits. Emergence of aging-related extinction deficits paralleled a redistribution of neuronal excitability across two critical mPFC regions via two distinct mechanisms. First, excitability decreased in regular spiking neurons of infralimbic-mPFC (IL), a region whose activity is required for extinction. Second, excitability increased in burst spiking neurons of prelimbic-mPFC (PL), a region whose activity hinders extinction. Experiments using synaptic blockers revealed that these aging-related differences were intrinsic. Thus, changes in IL and PL intrinsic excitability may contribute to cognitive flexibility impairments observed during normal aging.
Intercalated (ITC) amygdala neurons are thought to play a critical role in the extinction of conditioned fear. However, several factors hinder progress in studying ITC contributions to extinction. First, although extinction is usually studied in rats and mice, most ITC investigations were performed in guinea pigs or cats. Thus it is unclear whether their connectivity is similar across species. Second, we lack criteria to identify ITC cells on the basis of their discharge pattern. As a result, key predictions of ITC extinction models remain untested. Among these, ITC cells were predicted to be strongly excited by infralimbic inputs, explaining why infralimbic inhibition interferes with extinction. To study the connectivity of ITC cells, we labeled them with neurobiotin during patch recordings in slices of the rat amygdala. This revealed that medially located ITC cells project topographically to the central nucleus and to other ITC clusters located more ventrally. To study the infralimbic responsiveness of ITC cells, we performed juxtacellular recording and labeling of amygdala cells with neurobiotin in anesthetized rats. All ITC cells were orthodromically responsive to infralimbic stimuli, and their responses usually consisted of high-frequency (~350 Hz) trains of four to six spikes, a response pattern never seen in neighboring amygdala nuclei. Overall, our results suggest that the connectivity of ITC cells is conserved across species and that ITC cells are strongly responsive to infralimbic stimuli, as predicted by extinction models. The unique response pattern of ITC cells to infralimbic stimuli can now be used to identify them in fear conditioning experiments.
It has been suggested that reduced infralimbic (IL) cortical activity contributes to impairments of fear extinction. We therefore explored whether pharmacological activation of the IL would facilitate extinction under conditions it normally fails (i.e., immediate extinction). Rats received auditory fear conditioning 1 h before extinction training. Immediately prior to extinction, rats received microinfusions into the IL of the GABA(A) receptor antagonist, picrotoxin, or the NMDA receptor partial agonist, D-cycloserine. Although neither drug facilitated extinction, they both facilitated the subsequent re-extinction of fear when animals were trained in a drug-free state, suggesting that activating the IL primes behavioral extinction.
Human imaging studies examining fear conditioning have mainly focused on the neural responses to conditioned cues. In contrast, the neural basis of the unconditioned response and the mechanisms by which fear modulates inter-regional functional coupling have received limited attention. We examined the neural responses to an unconditioned stimulus using a partial-reinforcement fear conditioning paradigm and functional MRI. The analysis focused on: (1) the effects of an unconditioned stimulus (an electric shock) that was either expected and actually delivered, or expected but not delivered, and (2) on how related brain activity changed across conditioning trials, and (3) how shock expectation influenced inter-regional coupling within the fear network. We found that: (1) the delivery of the shock engaged the red nucleus, amygdale, dorsal striatum, insula, somatosensory and cingulate cortices, (2) when the shock was expected but not delivered, only the red nucleus, the anterior insular and dorsal anterior cingulate cortices showed activity increases that were sustained across trials, and (3) psycho-physiological interaction analysis demonstrated that fear led to increased red nucleus coupling to insula but decreased hippocampus coupling to the red nucleus, thalamus and cerebellum. The hippocampus and the anterior insula may serve as hubs facilitating the switch between engagement of a defensive immediate fear network and a resting network.
Some psychiatric illnesses involve a learned component. For example, in posttraumatic stress disorder, memories triggered by trauma-associated cues trigger fear and anxiety, and in addiction, drug-associated cues elicit drug craving and withdrawal. Clinical interventions to reduce the impact of conditioned cues in eliciting these maladaptive conditioned responses are likely to be beneficial. Extinction is a method of lessening conditioned responses and involves repeated exposures to a cue in the absence of the event it once predicted. We believe that an improved understanding of the behavioral and neurobiological mechanisms of extinction will allow extinction-like procedures in the clinic to become more effective. Research on the role of glutamate—the major excitatory neurotransmitter in the mammalian brain—in extinction has led to the development of pharmacotherapeutics to enhance the efficacy of extinction-based protocols in clinical populations. In this review, we describe what has been learned about glutamate actions at its three major receptor types (N-methyl--aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and metabotropic glutamate receptors) in the extinction of conditioned fear, drug craving, and withdrawal. We then discuss how these findings have been applied in clinical research.
Research employing aversive conditioning paradigms has elucidated the neurocircuitry involved in acquiring and diminishing fear responses. However, the factors underlying individual differences in fear acquisition and inhibition are not presently well understood. In this study, we explored whether the magnitude of individuals' acquired fear responses and the modulation of these responses via 2 fear reduction methods were correlated with structural differences in brain regions involved in affective processing. Physiological and structural magnetic resonance imaging data were obtained from experiments exploring extinction retention and intentional cognitive regulation. Our results identified 2 regions in which individual variation in brain structure correlated with subjects' fear-related arousal. Confirming previous results, increased thickness in ventromedial prefrontal cortex was correlated with the degree of extinction retention. Additionally, subjects with greater thickness in the posterior insula exhibited larger conditioned responses during acquisition. The data suggest a trend toward a negative correlation between amygdala volume and fear acquisition magnitude. There was no significant correlation between fear reduction via cognitive regulation and thickness in our prefrontal regions of interest. Acquisition and regulation measures were uncorrelated, suggesting that while certain individuals may have a propensity toward increased expression of conditioned fear, these responses can be diminished via both extinction and cognitive regulation.
Non-reinforced retrieval induces memory extinction, a phenomenon characterized by a decrease in the intensity of the learned response. This attribute has been used to develop extinction-based therapies to treat anxiety and post-traumatic stress disorders. Histamine modulates memory and anxiety but its role on fear extinction has not yet been evaluated. Therefore, using male Wistar rats, we determined the effect of the intra-hippocampal administration of different histaminergic agents on the extinction of step-down inhibitory avoidance (IA), a form of aversive learning. We found that intra-CA1 infusion of histamine immediately after non-reinforced retrieval facilitated consolidation of IA extinction in a dose-dependent manner. This facilitation was mimicked by the histamine N-methyltransferase inhibitor SKF91488 and the H2 receptor agonist dimaprit, reversed by the H2 receptor antagonist ranitidine, and unaffected by the H1 antagonist pyrilamine, the H3 antagonist thioperamide and the antagonist at the NMDA receptor (NMDAR) polyamine-binding site ifenprodil. Neither the H1 agonist 2-2-pyridylethylamine nor the NMDAR polyamine-binding site agonist spermidine affected the consolidation of extinction while the H3 receptor agonist imetit hampered it. Extinction induced the phosphorylation of ERK1 in dorsal CA1 while intra-CA1 infusion of the MEK inhibitor U0126 blocked extinction of the avoidance response. The extinction-induced phosphorylation of ERK1 was enhanced by histamine and dimaprit and blocked by ranitidine administered to dorsal CA1 after non-reinforced retrieval. Taken together, our data indicate that the hippocampal histaminergic system modulates the consolidation of fear extinction through a mechanism involving the H2-dependent activation of ERK signalling.
Negative emotional stimuli activate a broad network of brain regions, including the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. An early influential view dichotomized these regions into dorsal-caudal cognitive and ventral-rostral affective subdivisions. In this review, we examine a wealth of recent research on negative emotions in animals and humans, using the example of fear or anxiety, and conclude that, contrary to the traditional dichotomy, both subdivisions make key contributions to emotional processing. Specifically, dorsal-caudal regions of the ACC and mPFC are involved in appraisal and expression of negative emotion, whereas ventral-rostral portions of the ACC and mPFC have a regulatory role with respect to limbic regions involved in generating emotional responses. Moreover, this new framework is broadly consistent with emerging data on other negative and positive emotions.