scholarly journals Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model

2021 ◽  
Author(s):  
Kayla R. Nygaard ◽  
Raylynn G. Swift ◽  
Rebecca M. Glick ◽  
Rachael E. Wagner ◽  
Susan E. Maloney ◽  
...  
Keyword(s):  
Serotonin Transporter ◽  
Williams Syndrome ◽  
Conditioned Fear ◽  
Fear Memory ◽  
Receptor Activation ◽  
Oxytocin Receptor ◽  
Receptor Expression ◽  
Fear Learning ◽  
Underlying Mechanisms ◽  
Complete Deletion

ABSTRACTWilliams Syndrome is caused by a deletion of 26-28 genes on chromosome 7q11.23. Patients with this disorder have distinct behavioral phenotypes including learning deficits, anxiety, increased phobias, and hypersociability. Some studies also suggest elevated blood oxytocin and altered oxytocin receptor expression, and this oxytocin dysregulation is hypothesized to be involved in the underlying mechanisms driving a subset of these phenotypes. A ‘Complete Deletion’ mouse, modeling the hemizygous critical region deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These Complete Deletion mice also exhibited impaired fear responses in the conditioned fear task. Here, we address whether oxytocin dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an oxytocin receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in Complete Deletion mice. Thus, increased oxytocin signaling is not acutely responsible for this phenotype. We also evaluated oxytocin receptor and serotonin transporter availability in regions related to fear learning, memory, and sociability using autoradiography in wild type and Complete Deletion mice. While we identified trends in lowered oxytocin receptor expression in the lateral septal nucleus, and trends towards lowered serotonin transporter availability in the striatum and orbitofrontal cortex, we found no significant differences after correction. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus.

Acquisition of Fear and Extinction in Lateral Amygdala: A Modeling Study

2010 ◽  
Author(s):  
Sandeep Pendyam ◽  
Dongbeom Kim ◽  
Gregory J. Quirk ◽  
Satish S. Nair
Keyword(s):  
Pyramidal Neurons ◽  
Conditioned Fear ◽  
Fear Memory ◽  
Fear Learning ◽  
Cell Populations ◽  
Storage Site ◽  
Somatosensory Information ◽  
Cortical Inputs ◽  
Lateral Nucleus ◽  
And Storage

The lateral nucleus of amygdala (LA) is known to be a critical storage site for conditioned fear memory. Synaptic plasticity at auditory inputs to the dorsal LA (LAd) is critical for the formation and storage of auditory fear memories. Recent evidence suggests that two different cell populations (transient- and long-term plastic cells) are present in LAd and are responsible for fear learning. However, the mechanisms involved in the formation and storage of fear are not well understood. As an extension of previous work, a biologically realistic computational model of the LAd circuitry is developed to investigate these mechanisms. The network model consists of 52 LA pyramidal neurons and 13 interneurons. Auditory and somatosensory information reaches LA from both thalamic and cortical inputs. The model replicated the tone responses observed in the two LAd cell populations during conditioning and extinction. The model provides insights into the role of thalamic and cortical inputs in fear memory formation and storage.

scholarly journals Dopamine and fear memory formation in the human amygdala

2021 ◽  
Author(s):  
Andreas Frick ◽  
Johannes Björkstrand ◽  
Mark Lubberink ◽  
Allison Eriksson ◽  
Mats Fredrikson ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Dopamine Release ◽  
Conditioned Fear ◽  
Fear Memory ◽  
Memory Formation ◽  
Fear Learning ◽  
Causative Role ◽  
Endogenous Dopamine ◽  
Positron Emission ◽  
Endogenous Dopamine Release

AbstractLearning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.

scholarly journals Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model

2021 ◽  
Author(s):  
Kayla R. Nygaard ◽  
Raylynn G. Swift ◽  
Rebecca M. Glick ◽  
Rachael E. Wagner ◽  
Susan E. Maloney ◽  
...  
Keyword(s):  
Williams Syndrome ◽  
Receptor Activation ◽  
Oxytocin Receptor

scholarly journals Mas Receptor Activation Attenuates Allergic Airway Inflammation via Inhibiting JNK/CCL2-induced Macrophage Recruitment

2020 ◽  
Author(s):  
Luna Hong ◽  
Ming Chen ◽  
Jianting Shi ◽  
Qiujie Wang ◽  
Yimin Guo ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Epithelial Cell Line ◽  
Mas Receptor ◽  
Mapk Pathways ◽  
Underlying Mechanisms

Abstract Background: Defective absorption of acute allergic airway inflammation is involved in the initiation and development of chronic asthma. After allergen exposure, there is a rapid recruitment of macrophages around the airways, which promote acute inflammatory responses. The Ang-(1-7)/Mas receptor axis reportedly plays protective roles in various tissue inflammation and remodeling processes in vivo. However, the exact role of Mas receptor and their underlying mechanisms during the pathology of acute allergic airway inflammation remains unclear. Methods: Mas receptor expression was assessed in ovalbumin-induced acute asthmatic murine model. Then we estimated the anti-inflammatory role of Mas receptor in vivo and explored expressions of several known inflammatory cytokines as well as phosphorylation levels of MAPK pathways. Mas receptor functions and underlying mechanisms were studied further in the human bronchial epithelial cell line (16HBE).Results: Mas receptor expression decreased in acute allergic airway inflammation. Multiplex immunofluorescence co-localized Mas receptor and EpCAM, indicated that Mas receptor may function in the bronchial epithelium. Activating Mas receptor through AVE0991 significantly alleviated macrophage infiltration in airway inflammation, accompanied with down-regulation of CCL2 and phosphorylation levels of MAPK pathways. Further studies in 16HBE showed that AVE0991 pre-treatment inhibited LPS-induced or anisomycin-induced CCL2 increase and THP-1 macrophages migration via JNK pathways.Conclusion: Our findings suggested that Mas receptor activation significantly attenuated CCL2 dependent macrophage recruitments in acute allergic airway inflammation through JNK pathways, which indicated that Mas receptor, CCL2 and phospho-JNK could be potential targets against allergic airway inflammation.

scholarly journals Plastic Synaptic Networks of the Amygdala for the Acquisition, Expression, and Extinction of Conditioned Fear

2010 ◽  
Vol 90 (2) ◽  
pp. 419-463 ◽  
Author(s):  
Hans-Christian Pape ◽  
Denis Pare
Keyword(s):  
Conditioned Fear ◽  
Fear Memory ◽  
Network Activity ◽  
Fear Learning ◽  
Learning Mechanisms ◽  
Memory Extinction ◽  
Basic Biology ◽  
Learned Fear ◽  
Neuronal Systems ◽  
Neuronal Functions

The last 10 years have witnessed a surge of interest for the mechanisms underlying the acquisition and extinction of classically conditioned fear responses. In part, this results from the realization that abnormalities in fear learning mechanisms likely participate in the development and/or maintenance of human anxiety disorders. The simplicity and robustness of this learning paradigm, coupled with the fact that the underlying circuitry is evolutionarily well conserved, make it an ideal model to study the basic biology of memory and identify genetic factors and neuronal systems that regulate the normal and pathological expressions of learned fear. Critical advances have been made in determining how modified neuronal functions upon fear acquisition become stabilized during fear memory consolidation and how these processes are controlled in the course of fear memory extinction. With these advances came the realization that activity in remote neuronal networks must be coordinated for these events to take place. In this paper, we review these mechanisms of coordinated network activity and the molecular cascades leading to enduring fear memory, and allowing for their extinction. We will focus on Pavlovian fear conditioning as a model and the amygdala as a key component for the acquisition and extinction of fear responses.

scholarly journals Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

2019 ◽  
Author(s):  
Nathan Kopp ◽  
Katherine McCullough ◽  
Susan E. Maloney ◽  
Joseph D. Dougherty
Keyword(s):  
Mouse Model ◽  
Williams Syndrome ◽  
Critical Region ◽  
Conditioned Fear ◽  
Neurodevelopmental Disorder ◽  
Transcriptome Profiling ◽  
Loss Of Function ◽  
Motor Functioning ◽  
Visual Spatial ◽  
Complete Deletion

AbstractWilliams syndrome is a neurodevelopmental disorder caused by a 1.5-1.8Mbp deletion on chromosome 7q11.23, affecting the copy number of 26-28 genes. Phenotypes of Williams syndrome include cardiovascular problems, craniofacial dysmorphology, deficits in visual spatial cognition, and a characteristic hypersocial personality. There are still no genes in the region that have been consistently linked to the cognitive and behavioral phenotypes, although human studies and mouse models have led to the current hypothesis that the general transcription factor 2 I family of genes, GTF2I and GTF2IRD1, are responsible. Here we test the hypothesis that these two transcription factors are sufficient to reproduce the phenotypes that are caused by deletion of the Williams syndrome critical region (WSCR). We compare a new mouse model with loss of function mutations in both Gtf2i and Gtf2ird1 to an established mouse model lacking the complete WSCR. We show that the complete deletion model has deficits across several behavioral domains including social communication, motor functioning, and conditioned fear that are not explained by loss of function mutations in Gtf2i and Gtf2ird1. Furthermore, transcriptome profiling of the hippocampus shows changes in synaptic genes in the complete deletion model that are not seen in the double mutants. Thus, we have thoroughly defined a set of molecular and behavioral consequences of complete WSCR deletion, and shown that other genes or combinations of genes are necessary to produce these phenotypic effects.

scholarly journals Dopamine facilitates fear memory formation in the human amygdala

2021 ◽  
Author(s):  
Andreas Frick ◽  
Johannes Björkstrand ◽  
Mark Lubberink ◽  
Allison Eriksson ◽  
Mats Fredrikson ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Dopamine Release ◽  
Conditioned Fear ◽  
Fear Memory ◽  
Memory Formation ◽  
Fear Learning ◽  
Causative Role ◽  
Endogenous Dopamine ◽  
Positron Emission ◽  
Endogenous Dopamine Release

ABSTRACTLearning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced memory trace activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.

A Retrieval-Extinction Paradigm to Treat Conditioned Fear Memory

2014 ◽  
Vol 22 (3) ◽  
pp. 431
Author(s):  
Xiangxing ZENG ◽  
Yanhui XIANG ◽  
Juan DU ◽  
Xifu ZHENG
Keyword(s):  
Conditioned Fear ◽  
Fear Memory

scholarly journals Observational Fear Learning in Rats: Role of Trait Anxiety and Ultrasonic Vocalization

2021 ◽  
Vol 11 (4) ◽  
pp. 423
Author(s):  
Markus Fendt ◽  
Claudia Paulina Gonzalez-Guerrero ◽  
Evelyn Kahl
Keyword(s):  
Trait Anxiety ◽  
Conditioned Fear ◽  
Ultrasonic Vocalization ◽  
Fear Learning ◽  
Anxiety State ◽  
Learning Procedure ◽  
The Social ◽  
Medium Level ◽  
Male Wistar Rats

Rats can acquire fear by observing conspecifics that express fear in the presence of conditioned fear stimuli. This process is called observational fear learning and is based on the social transmission of the demonstrator rat’s emotion and the induction of an empathy-like or anxiety state in the observer. The aim of the present study was to investigate the role of trait anxiety and ultrasonic vocalization in observational fear learning. Two experiments with male Wistar rats were performed. In the first experiment, trait anxiety was assessed in a light–dark box test before the rats were submitted to the observational fear learning procedure. In the second experiment, ultrasonic vocalization was recorded throughout the whole observational fear learning procedure, and 22 kHz and 50 kHz calls were analyzed. The results of our study show that trait anxiety differently affects direct fear learning and observational fear learning. Direct fear learning was more pronounced with higher trait anxiety, while observational fear learning was the best with a medium-level of trait anxiety. There were no indications in the present study that ultrasonic vocalization, especially emission of 22 kHz calls, but also 50 kHz calls, are critical for observational fear learning.

scholarly journals Fear conditioning and stimulus generalization in association with age in children and adolescents

2021 ◽  
Author(s):  
Julia Reinhard ◽  
Anna Slyschak ◽  
Miriam A. Schiele ◽  
Marta Andreatta ◽  
Katharina Kneer ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Fear Conditioning ◽  
Repeated Measures ◽  
Conditioned Fear ◽  
Fear Learning ◽  
Stimulus Generalization ◽  
Healthy Children ◽  
Older Individuals ◽  
Age Related ◽  
Current Task

AbstractThe aim of the study was to investigate age-related differences in fear learning and generalization in healthy children and adolescents (n = 133), aged 8–17 years, using an aversive discriminative fear conditioning and generalization paradigm adapted from Lau et al. (2008). In the current task, participants underwent 24 trials of discriminative conditioning of two female faces with neutral facial expressions, with (CS+) or without (CS−) a 95-dB loud female scream, presented simultaneously with a fearful facial expression (US). The discriminative conditioning was followed by 72 generalization trials (12 CS+, 12 GS1, 12 GS2, 12 GS3, 12 GS4, and 12 CS−): four generalization stimuli depicting gradual morphs from CS+ to CS− in 20%-steps were created for the generalization phases. We hypothesized that generalization in children and adolescents is negatively correlated with age. The subjective ratings of valence, arousal, and US expectancy (the probability of an aversive noise following each stimulus), as well as skin conductance responses (SCRs) were measured. Repeated-measures ANOVAs on ratings and SCR amplitudes were calculated with the within-subject factors stimulus type (CS+, CS−, GS1-4) and phase (Pre-Acquisition, Acquisition 1, Acquisition 2, Generalization 1, Generalization 2). To analyze the modulatory role of age, we additionally calculated ANCOVAs considering age as covariate. Results indicated that (1) subjective and physiological responses were generally lower with increasing age irrespective to the stimulus quality, and (2) stimulus discrimination improved with increasing age paralleled by reduced overgeneralization in older individuals. Longitudinal follow-up studies are required to analyze fear generalization with regard to brain maturational aspects and clarify whether overgeneralization of conditioned fear promotes the development of anxiety disorders or vice versa.

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