Fear extinction learning and anandamide: an fMRI study in healthy humans

AbstractAnxiety- and trauma-related disorders are severe illnesses with high prevalence. Current treatment options leave room for improvement and the endocannabinoid system (ECS) has become a key target in psychopharmacological research. Rodent models suggest an anxiolytic effect of endocannabinoids and demonstrated that the ECS is involved in the modulation of fear learning and aversive memory consolidation. So far, one prominent target was inhibition of fatty acid amino hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide (AEA). Research in humans remains scarce, but genetic studies have found that the single-nucleotide polymorphism (SNP) FAAH C385A (rs324420) is associated with lower catabolic performance of FAAH and increased levels of AEA. Translational research on the ECS in fear learning processes is rare, yet crucial to understand the mechanisms involved. To address this lack of research, we designed a fear conditioning, extinction learning paradigm with 51 healthy, male humans who underwent functional magnetic resonance imaging (fMRI) before analysing baseline and task-related changes of AEA, as well as the FAAH polymorphism (rs324420). The results indicate higher AEA levels in AC-heterozygotes than in CC-individuals (SNP rs324420), but no difference between the groups during extinction learning. However, neural activation of the anterior cingulate cortex and anterior insular cortex during extinction learning correlated positively with AEA baseline levels, and task-related changes in AEA were found particularly during fear extinction, with a modulatory effect on neural activation related to extinction learning. Results indicate a putative role for AEA in fear extinction learning. Pre-treatment with AEA-enhancing drugs could promote extinction learning during psychotherapeutic interventions.

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FAAH polymorphism (rs324420) modulates extinction recall in healthy humans: an fMRI study

European Archives of Psychiatry and Clinical Neuroscience ◽

10.1007/s00406-021-01367-4 ◽

2021 ◽

Author(s):

Jennifer Spohrs ◽

Martin Ulrich ◽

Georg Grön ◽

Paul L. Plener ◽

Birgit Abler

Keyword(s):

Fatty Acid Amide Hydrolase ◽

Acid Amide ◽

Endocannabinoid System ◽

Insular Cortex ◽

Anterior Cingulate ◽

Neural Activation ◽

Extinction Learning ◽

Healthy Humans ◽

Fmri Study ◽

Amide Hydrolase

AbstractGold standard treatments for anxiety- and trauma-related disorders focus on exposure therapy promoting extinction learning and extinction retention. However, its efficacy is limited. Preclinical and particularly animal research has been able to demonstrate that homozygosity for the fatty acid amide hydrolase (FAAH) C385A allele, similar to FAAH inhibition, is associated with elevated concentrations of anandamide (AEA) and facilitates extinction learning and extinction recall. However, in humans, the underlying neurobiological processes are less well understood, and further knowledge might enhance the development of more effective therapies. In this functional magnetic resonance imaging (fMRI) study, a fear conditioning, fear extinction and extinction recall paradigm was conducted with 55 healthy male adults. They were genotyped for the FAAH single-nucleotide polymorphism (SNP) rs324420 to investigate differences related to extinction recall in neural activation and State–Trait Anxiety Inventory (STAI) ratings between AC heterozygotes and CC homozygotes (FAAH C385A SNP). Differential brain activation upon an unextinguished relative to an extinguished stimulus, was greater in AC heterozygotes as compared to CC homozygotes in core neural structures previously related to extinction recall, such as the medial superior frontal gyrus, the dorsal anterior cingulate and the anterior and middle insular cortex. Furthermore, AC heterozygotes displayed higher AEA levels and lower STAI-state ratings. Our data can be interpreted in line with previous suggestions of more successful extinction recall in A-allele carriers with elevated AEA levels. Data corroborate the hypothesis that the endocannabinoid system, particularly AEA, plays a modulatory role in the extinction of aversive memory.

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GluN2D NMDA Receptors Gate Fear Extinction Learning and Interneuron Plasticity

Frontiers in Synaptic Neuroscience ◽

10.3389/fnsyn.2021.681068 ◽

2021 ◽

Vol 13 ◽

Author(s):

Christophe J. Dubois ◽

Siqiong June Liu

Keyword(s):

Nmda Receptor ◽

Fear Conditioning ◽

Learning And Memory ◽

Molecular Layer ◽

Gaba Release ◽

Long Term Potentiation ◽

Fear Extinction ◽

Fear Learning ◽

Inhibitory Synapses ◽

Extinction Learning

The cerebellum is critically involved in the formation of associative fear memory and in subsequent extinction learning. Fear conditioning is associated with a long-term potentiation at both excitatory and inhibitory synapses onto Purkinje cells. We therefore tested whether fear conditioning unmasks novel forms of synaptic plasticity, which enable subsequent extinction learning to reset cerebellar circuitry. We found that fear learning enhanced GABA release from molecular layer interneurons and this was reversed after fear extinction learning. Importantly an extinction-like stimulation of parallel fibers after fear learning is sufficient to induce a lasting decrease in inhibitory transmission (I-LTDstim) in the cerebellar cortex, a form of plasticity that is absent in naïve animals. While NMDA (N-methyl-D-aspartate) receptors are required for the formation and extinction of associative memory, the role of GluN2D, one of the four major NMDA receptor subunits, in learning and memory has not been determined. We found that fear conditioning elevates spontaneous GABA release in GluN2D KO as shown in WT mice. Deletion of GluN2D, however, abolished the I-LTDstim induced by parallel fiber stimulation after learning. At the behavioral level, genetic deletion of GluN2D subunits did not affect associative learning and memory retention, but impaired subsequent fear extinction learning. D-cycloserine, a partial NMDA receptor (NMDAR) agonist, failed to rescue extinction learning in mutant mice. Our results identify GluN2D as a critical NMDAR subunit for extinction learning and reveal a form of GluN2D-dependent metaplasticity that is associated with extinction in the cerebellum.

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Overnight fasting affects avoidance learning and relief

10.31234/osf.io/muz38 ◽

2021 ◽

Author(s):

Silvia Papalini ◽

Neefs Laura ◽

Tom Beckers ◽

Lukas Van Oudenhove ◽

Bram Vervliet

Keyword(s):

Avoidance Learning ◽

Fear Extinction ◽

Reward Processing ◽

Fear Learning ◽

Prolonged Fasting ◽

Extinction Learning ◽

Dopaminergic Activity ◽

Future Studies ◽

Overnight Fasting ◽

Fundamental Systems

Prolonged fasting influences threat and reward processing, two fundamental systems underpinning adaptive behaviors. In animals, overnight fasting sensitizes the mesolimbic-dopaminergic activity governing avoidance, reward, and fear-extinction learning. Despite evidence that overnight fasting may also affect reward and fear learning in humans, effects on human avoidance learning have not been studied yet. Here, we examined the effects of 16h-overnight fasting on instrumental avoidance and relief from threat omission. To this end, 50 healthy women were randomly assigned to a fasting (N=25) or a re-feeding group (N=25) and performed an Avoidance-Relief Task. We found that fasting decreases unnecessary avoidance during signaled safety; this effect was mediated via a reduction in relief pleasantness during signaled absence of threat. A fasting-induced reduction in relief was also found during fear extinction learning. We conclude that fasting optimizes avoidance and safety learning. Future studies should test whether these effects also hold for anxious individuals.

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Estradiol and Sex Differences in Generalized Fear

Estrogens and Memory ◽

10.1093/oso/9780190645908.003.0026 ◽

2020 ◽

pp. 433-455

Author(s):

Jordan M. Adkins ◽

Aaron M. Jasnow ◽

Joseph F. Lynch

Keyword(s):

Sex Differences ◽

Anxiety Disorders ◽

Critical Role ◽

Fear Extinction ◽

Anterior Cingulate ◽

Female Rats ◽

Fear Learning ◽

Ca1 Region ◽

Glutamatergic Signaling ◽

Fear Generalization

In the United States, the prevalence of psychiatric disorders has reached nearly epidemic proportions. Years of research has focused on the link between 17β‎-estradiol and the sex differences observed in anxiety disorders. Evidence suggests that estradiol plays a critical role in the way female rodents and women respond in various tasks assessing anxiety-like behaviors, fear learning, and fear extinction. One hallmark feature of many anxiety disorders is the tendency to express fear to nonthreatening contexts or cues. This generalized fear supports spreading of fear responses and can serve to maintain anxiety states. This chapter reviews the literature linking estradiol to anxiety behavior in female rodents and anxiety in women, including research on estradiol in fear learning and fear extinction. The chapter also presents data suggesting that female rats generalize fear at a faster rate than males, and this is due to estradiol. Through a series of experiments, the authors determine that estradiol promotes contextual fear generalization in female rats through activation of cytosolic estrogen receptor beta (ERβ‎) within the dorsal CA1 region of the hippocampus (dCA1). Additionally, estradiol promotes fear generalization likely through augmented glutamatergic signaling within the dCA1 and anterior cingulate cortex (ACC). However, in males, estradiol (and testosterone) function to reduce fear generalization and do so by activation of both ERβ‎ and ERα‎ within the dCA1. Understanding the neural mechanisms underlying the critical role of estradiol in context fear generalization will yield the knowledge and information necessary for developing novel, sex-specific, treatments for anxiety disorders.

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Effects of Delta9-tetrahydrocannabinol (THC) on Retention of Memory for Fear Extinction Learning in PTSD: R33 Study

Case Medical Research ◽

10.31525/ct1-nct04080427 ◽

2019 ◽

Author(s):

Keyword(s):

Fear Extinction ◽

Extinction Learning

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Control of impulsivity by Gi-protein signalling in layer-5 pyramidal neurons of the anterior cingulate cortex

Communications Biology ◽

10.1038/s42003-021-02188-w ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Bastiaan van der Veen ◽

Sampath K. T. Kapanaiah ◽

Kasyoka Kilonzo ◽

Peter Steele-Perkins ◽

Martin M. Jendryka ◽

...

Keyword(s):

Gene Expression ◽

Anterior Cingulate Cortex ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Pyramidal Neurons ◽

Treatment Options ◽

Pyramidal Cells ◽

Cingulate Cortex ◽

Cell Types ◽

Anterior Cingulate

AbstractPathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of Gi-signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among Gi-coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest Gi-coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

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Peripheral BDNF: a candidate biomarker of healthy neural activity during learning is disrupted in schizophrenia

Psychological Medicine ◽

10.1017/s0033291714001925 ◽

2014 ◽

Vol 45 (4) ◽

pp. 841-854 ◽

Cited By ~ 13

Author(s):

A. J. Skilleter ◽

C. S. Weickert ◽

A. Vercammen ◽

R. Lenroot ◽

T. W. Weickert

Keyword(s):

Functional Neuroimaging ◽

Brain Activity ◽

Healthy Adults ◽

Enzyme Linked Immunosorbent Assay ◽

Association Learning ◽

Healthy Humans ◽

Important Regulator ◽

Learning Test ◽

Parietal Cortices ◽

And Task

Background.Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptogenesis and synaptic plasticity underlying learning. However, a relationship between circulating BDNF levels and brain activity during learning has not been demonstrated in humans. Reduced brain BDNF levels are found in schizophrenia and functional neuroimaging studies of probabilistic association learning in schizophrenia have demonstrated reduced activity in a neural network that includes the prefrontal and parietal cortices and the caudate nucleus. We predicted that brain activity would correlate positively with peripheral BDNF levels during probabilistic association learning in healthy adults and that this relationship would be altered in schizophrenia.Method.Twenty-five healthy adults and 17 people with schizophrenia or schizo-affective disorder performed a probabilistic association learning test during functional magnetic resonance imaging (fMRI). Plasma BDNF levels were measured by enzyme-linked immunosorbent assay (ELISA).Results.We found a positive correlation between circulating plasma BDNF levels and brain activity in the parietal cortex in healthy adults. There was no relationship between plasma BDNF levels and task-related activity in the prefrontal, parietal or caudate regions in schizophrenia. A direct comparison of these relationships between groups revealed a significant diagnostic difference.Conclusions.This is the first study to show a relationship between peripheral BDNF levels and cortical activity during learning, suggesting that plasma BDNF levels may reflect learning-related brain activity in healthy humans. The lack of relationship between plasma BDNF and task-related brain activity in patients suggests that circulating blood BDNF may not be indicative of learning-dependent brain activity in schizophrenia.

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Correlation between Traits of Emotion-Based Impulsivity and Intrinsic Default-Mode Network Activity

Neural Plasticity ◽

10.1155/2017/9297621 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 11

Author(s):

Jizheng Zhao ◽

Dardo Tomasi ◽

Corinde E. Wiers ◽

Ehsan Shokri-Kojori ◽

Şükrü B. Demiral ◽

...

Keyword(s):

Brain Activity ◽

Low Frequency ◽

Cingulate Cortex ◽

Posterior Cingulate Cortex ◽

Anterior Cingulate ◽

Network Activity ◽

High Risk Behaviors ◽

Posterior Cingulate ◽

Healthy Humans ◽

Dorsolateral Prefrontal

Negative urgency (NU) and positive urgency (PU) are implicated in several high-risk behaviors, such as eating disorders, substance use disorders, and nonsuicidal self-injury behavior. The current study aimed to explore the possible link between trait of urgency and brain activity at rest. We assessed the amplitude of low-frequency fluctuations (ALFF) of the resting-state functional magnetic resonance imaging (fMRI) signal in 85 healthy volunteers. Trait urgency measures were related to ALFF in the lateral orbitofrontal cortex, dorsolateral prefrontal cortex, ventral and dorsal medial frontal cortex, anterior cingulate, and posterior cingulate cortex/precuneus. In addition, trait urgency measures showed significant correlations with the functional connectivity of the posterior cingulate cortex/precuneus seed with the thalamus and midbrain region. These findings suggest an association between intrinsic brain activity and impulsive behaviors in healthy humans.

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