Role of Human Ventromedial Prefrontal Cortex in Learning and Recall of Enhanced Extinction

Dunsmoor, Joseph E.; Kroes, Marijn C. W.; Li, Jian; Daw, Nathaniel D.; Simpson, Helen Blair; Phelps, Elizabeth A.

doi:10.1523/jneurosci.2713-18.2019

Cited by 79 publications

(70 citation statements)

References 81 publications

(106 reference statements)

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“…Overall, imposing a 7-day delay after fear conditioning did not appear to alter the extinction or discrimination learning phenotype relative to training on consecutive days (Figure 2). 60 From a neurophysiological perspective, one hypothesis to be tested is that using a daily novel context may retain the engagement of neural circuits underlying extinction learning that usually attenuate after the first day of training in the same context. 58,59 In light of our results suggesting that changing the quality of the CS was effective in modulating maladaptive fear, we tested the possibility that extinction training within a daily novel context might enhance consolidation of extinction memories.…”

Section: Discussionmentioning

confidence: 99%

“…In support of this idea, a recent study in humans finds that replacing a threat stimulus with a novel stimulus facilitates extinction learning by engaging ventromedial prefrontal cortex. 60 From a neurophysiological perspective, one hypothesis to be tested is that using a daily novel context may retain the engagement of neural circuits underlying extinction learning that usually attenuate after the first day of training in the same context. 9,55,57 These results may also have important implications for the effectiveness of cognitive-behavioral therapies based on extinction learning, such as those used to treat PTSD.…”

Section: Discussionmentioning

confidence: 99%

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Environmental variables that ameliorate extinction learning deficits in the 129S1/SvlmJ mouse strain

Cazares

Rodriguez

Parent

et al. 2019

Genes Brain and Behavior

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Fear conditioning is an associative learning process by which organisms learn to avoid environmental stimuli that are predictive of aversive outcomes. Fear extinction learning is a process by which avoidance of fear‐conditioned stimuli is attenuated when the environmental stimuli is no longer predictive of the aversive outcome. Aberrant fear conditioning and extinction learning are key elements in the development of several anxiety disorders. The 129S1 inbred strain of mice is used as an animal model for maladaptive fear learning because this strain has been shown to generalize fear to other nonaversive stimuli and is less capable of extinguishing fear responses relative to other mouse strains, such as the C57BL/6. Here we report new environmental manipulations that enhance fear and extinction learning, including the ability to discriminate between an aversively paired tone and a neutral tone, in both the 129S1 and C57BL/6 strains of mice. Specifically, we show that discontinuous (“pipped”) tone stimuli significantly enhance within‐session extinction learning and the discrimination between neutral and aversively paired stimuli in both strains. Furthermore, we find that extinction training in novel contexts significantly enhances the consolidation and recall of extinction learning for both strains. Cumulatively, these results underscore how environmental changes can be leveraged to ameliorate maladaptive learning in animal models and may advance cognitive and behavioral therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Environmental variables that ameliorate extinction learning deficits in the 129S1/SvlmJ mouse strain

Cazares

Rodriguez

Parent

et al. 2019

Genes Brain and Behavior

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“…amygdala, cingulate cortex, insula; see Phan KL et al 2002) during dreaming, the weaker the reaction of these same regions to actual fear-eliciting stimuli during wakefulness should be. This compensatory or homeostatic mechanism may also be accompanied by an enhanced recruitment of emotion regulation brain regions (such as the medial prefrontal cortex, mPFC, which is implicated in fear extinction) during wakefulness (Quirk GJ et al 2003;Phelps EA et al 2004;Yoo SS et al 2007;Dunsmoor JE et al 2019).Here, we collected dream reports and functional brain measures using high-density EEG (hdEEG) and functional MRI (fMRI) across two studies to address the following questions: (i) do emotions in dreams (here fear-related emotions) engage the same neural circuits as during wakefulness, and (ii) is there a link between emotions experienced in dreams and brain responses to emotional stimuli during wakefulness. By addressing these fundamental and complementary topics, we aim at clarifying the grounding conditions for the study of dreaming as pertaining to day/night affective homeostasis.…”

mentioning

confidence: 99%

Fear in dreams and in wakefulness: evidence for day/night affective homeostasis

Sterpenich

Perogamvros

Tononi

et al. 2019

Preprint

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Recent neuroscientific theories have proposed that emotions experienced in dreams contribute to the resolution of emotional distress and preparation for future affective reactions. We addressed one emerging prediction, namely that experiencing fear in dreams is associated with more adapted responses to threatening signals during wakefulness. Using a stepwise approach across two studies, we identified brain regions activated when experiencing fear in dreams and showed that frightening dreams modulated the response of these same regions to threatening stimuli during wakefulness. Specifically, in Study 1, we performed serial awakenings in 18 participants recorded throughout the night with highdensity EEG and asked them whether they experienced any fear in their dreams. Insula and midcingulate cortex activity increased for dreams containing fear. In Study 2, we tested 89 participants and found that those reporting higher incidence of fear in their dreams showed reduced emotional arousal and fMRI response to fear-eliciting stimuli in the insula, amygdala and midcingulate cortex, while awake. Consistent with better emotion regulation processes, the same participants displayed increased medial prefrontal cortex activity. These findings support that emotions in dreams and wakefulness engage similar neural substrates, and substantiate a link between emotional processes occurring during sleep and emotional brain functions during wakefulness. SIGNIFICANT STATEMENTHighly debated while pivotal to current theoretical models of dreaming, the relationship between emotion processing during wakefulness and in dreams remains elusive. In a first study, we used high-density EEG recordings and observed that regions involved in fear processing (i.e. the insula and midcingulate cortex) were activated during fear-related dreams. This first finding demonstrates that emotions in dreams engage similar neural circuits as during wakefulness. In a second study, using fMRI, we show that higher incidence of fear in dreams was associated with reduced emotional arousal and brain responses indicative of better emotion regulation during wakefulness. Together, these results strongly support the idea that experiencing fear in a secure environment, as in dreams, relates to more adapted responses to threatening events in real life. 2000), others reported a balance of positive and negative emotions (Schredl M and E Doll 1998), or found that joy and emotions related to approach behaviors may prevail (Fosse R et al. 2001;Malcolm-Smith S et al. 2012). When performing a lexicostatistical analysis of large datasets of dream reports, a clear dissociation between dreams containing basic, mostly fear-related, emotions and those with other more social emotions (e.g. embarrassment, excitement, frustration) was found, highlighting distinct affective modes operating during dreaming, with fear in dreams representing a prevalent and biologically-relevant emotional category (Revonsuo A 2000;Schwartz S 2004). Thus, if fear-containing dreams serve an emotion regulation f...

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“…These results must be extended to other brain regions (e.g., ventromedial prefrontal cortex, shown to be integral to fear learning and extinction (Dunsmoor et al, 2019), processes hypothesized to be central to PTSD onset and recovery, respectively (Maddox et al, 2019;Shalev et al, 2017)) and replicated in additional samples. But the totality of the results now associating CRHR1 with PTSD severity across GWAS, GWGAS, imputed expression, and postmortem analyses, in concert with the strong preclinical and clinical priors for involvement of CRH in stress-related disorders (Chrousos and Zoumakis, 2017), position CRHR1 antagonists as strong therapeutic candidates for PTSD and related conditions.…”

Section: Discussionmentioning

confidence: 96%

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

Stein

Levey

Cheng

et al. 2019

Preprint

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Individuals vary in their liability to develop Posttraumatic Stress Disorder (PTSD), the symptoms of which are highly heterogeneous, following exposure to life-threatening trauma. Understanding genetic factors that contribute to the biology of PTSD is critical for refining diagnosis and developing new treatments. Using genetic data from more than 250,000 participants in the Million Veteran Program, genomewide association analyses were conducted using a validated electronic health record-based algorithmically-defined PTSD diagnosis phenotype (48,221 cases and 217,223 controls), and PTSD quantitative symptom phenotypes (212,007 individuals). We identified several genome-wide significant loci in the case-control analyses, and numerous such loci in the quantitative trait analyses, including some (e.g., MAD1L1; TCF4; CRHR1) that were associated with multiple symptom sub-domains and total symptom score, and others that were more specific to certain symptom sub-domains (e.g., CAMKV to reexperiencing; SOX6 to hyperarousal). Genetic correlations between all pairs of symptom sub-domains and their total were very high (rg 0.93 -0.98) supporting validity of the PTSD diagnostic construct. We also demonstrate strong shared heritability with a range of traits, show that heritability persists when conditioned on other major psychiatric disorders, present independent replication results, provide support for one of the implicated genes in postmortem brain of individuals with PTSD, and use this information to identify potential drug repositioning candidates. These results point to the utility of genetics to inform and validate the biological coherence of the PTSD syndrome despite considerable heterogeneity at the symptom level, and to provide new directions for treatment development.

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Role of Human Ventromedial Prefrontal Cortex in Learning and Recall of Enhanced Extinction

Cited by 79 publications

References 81 publications

Environmental variables that ameliorate extinction learning deficits in the 129S1/SvlmJ mouse strain

Environmental variables that ameliorate extinction learning deficits in the 129S1/SvlmJ mouse strain

Fear in dreams and in wakefulness: evidence for day/night affective homeostasis

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

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