Impact of ADCYAP1R1 genotype on longitudinal fear conditioning in children: interaction with trauma and sex.
Ontology highlight
ABSTRACT:
SUBMITTER: Jovanovic T
PROVIDER: S-EPMC7421882 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Few studies have explored interactions between genes and social environmental exposures (GxSEs) for trauma-related psychopathology, including symptoms of posttraumatic stress (PTS) and major depression (MD). The extant literature suggests the possibility of a GxSE between the rs2267735 variant of the ADCYAP1R1 gene and neighborhood crime. The current study aimed to explore this possibility among a predominantly African American sample of trauma-exposed women.Female participants (N=1361) were recruited from a public hospital, and completed measures of PTS and MD symptoms and provided DNA samples. Participants' home addresses were mapped onto 300 neighborhoods (2010 census tracts), and data on crime within neighborhoods was collected.Multilevel models detected a significant GxSE between rs2267735 and neighborhood crime for MD symptoms (p=.01). Having two copies of the risk (C) allele was associated with higher MD symptoms for participants living in high-crime neighborhoods.At least six limitations are noteworthy: (1) low statistical power; (2) use of self-report symptom inventories; (3) lack of information on symptom onset; (4) homogeneous sample from a single metropolitan area; (5) non-specific index of crime; and (6) use of census tracts to define neighborhoods.The results provide further evidence of GxSEs for psychiatric outcomes among trauma-exposed populations. Further investigations of genetic factors for trauma-related psychopathology should include careful assessments of the social environment.
| S-EPMC4587299 | biostudies-literature
Project description:Posttraumatic stress disorder (PTSD) is associated with dysfunction of the neural circuitry that supports fear learning and memory processes. However, much of what is known about neural dysfunction in PTSD is based on research in chronic PTSD populations. Less is known about neural function that supports fear learning acutely following trauma exposure. Determining the acute effects of trauma exposure on brain function would provide new insight into the neural processes that mediate the cognitive-affective dysfunction associated with PTSD. Therefore, the present study investigated neural activity that supports fear learning and memory processes in recently Trauma-Exposed (TE) and Non-Trauma-Exposed (NTE) participants. Participants completed a Pavlovian fear conditioning procedure during functional magnetic resonance imaging (fMRI). During fMRI, participants' threat expectancy was continuously monitored. NTE participants showed greater threat expectancy during warning than safety cues, while no difference was observed in the TE group. This finding suggests TE participants overgeneralized the fear association to the safety cue. Further, only the TE group showed a negative relationship between fMRI signal responses within dorsomedial prefrontal cortex (PFC) and threat expectancy during safety cues. These results suggest the dorsomedial PFC mediates overgeneralization of learned fear as an acute result of trauma exposure. Finally, neural activity within the PFC and inferior parietal lobule showed a negative relationship with PTSD symptom severity assessed three months posttrauma. Thus, neural activity measured acutely following trauma exposure predicted future PTSD symptom severity. The present findings elucidate the acute effects of trauma exposure on cognitive-affective function and provide new insight into the neural mechanisms of PTSD.
| S-EPMC6261786 | biostudies-literature
Project description:Women are twice as likely as men to develop Posttraumatic Stress Disorder (PTSD). Abnormal acquisition of conditioned fear has been suggested as a mechanism for the development of PTSD. While some studies of healthy humans suggest that women are either no different or express less conditioned fear responses during conditioning relative to men, differences in the acquisition of conditioned fear between men and women diagnosed with PTSD has not been examined.Thirty-one participants (18 men; 13 women) with full or subsyndromal PTSD completed a fear conditioning task. Participants were shown computer-generated colored circles that were paired (CS+) or unpaired (CS-) with an aversive electrical stimulus and skin conductance levels were assessed throughout the task.Repeated measures ANOVA indicated a significant sex by stimulus interaction during acquisition. Women had greater differential conditioned skin conductance responses (CS + trials compared to CS- trials) than did men, suggesting greater acquisition of conditioned fear in women with PTSD.In contrast to studies of healthy individuals, we found enhanced acquisition of conditioned fear in women with PTSD. Greater fear conditioning in women may either be a pre-existing vulnerability trait or an acquired phenomenon that emerges in a sex-dependent manner after the development of PTSD. Characterizing the underlying mechanisms of these differences is needed to clarify sex-related differences in the pathophysiology of PTSD.
| S-EPMC3806498 | biostudies-literature
Project description:Alterations in learning processes and the neural circuitry that supports fear conditioning and extinction represent mechanisms through which trauma exposure might influence risk for psychopathology. Few studies examine how trauma or neural structure relates to fear conditioning in children. Children (n=94) aged 6-18 years, 40.4% (n=38) with exposure to maltreatment (physical abuse, sexual abuse, or domestic violence), completed a fear conditioning paradigm utilizing blue and yellow bells as conditioned stimuli (CS+/CS-) and an aversive alarm noise as the unconditioned stimulus. Skin conductance responses (SCR) and self-reported fear were acquired. Magnetic resonance imaging data were acquired from 60 children. Children without maltreatment exposure exhibited strong differential conditioning to the CS+ vs CS-, based on SCR and self-reported fear. In contrast, maltreated children exhibited blunted SCR to the CS+ and failed to exhibit differential SCR to the CS+ vs CS- during early conditioning. Amygdala and hippocampal volume were reduced among children with maltreatment exposure and were negatively associated with SCR to the CS+ during early conditioning in the total sample, although these associations were negative only among non-maltreated children and were positive among maltreated children. The association of maltreatment with externalizing psychopathology was mediated by this perturbed pattern of fear conditioning. Child maltreatment is associated with failure to discriminate between threat and safety cues during fear conditioning in children. Poor threat-safety discrimination might reflect either enhanced fear generalization or a deficit in associative learning, which may in turn represent a central mechanism underlying the development of maltreatment-related externalizing psychopathology in children.
| S-EPMC4908632 | biostudies-other
Project description:Post-traumatic stress disorder (PTSD) is characterized in part by impaired extinction of conditioned fear. Traumatic brain injury (TBI) is thought to be a risk factor for development of PTSD. We tested the hypothesis that controlled cortical impact (CCI) would impair extinction of fear learned by Pavlovian conditioning, in mice. To mimic the scenarios in which TBI occurs prior to or after exposure to an aversive event, severe CCI was delivered to the left parietal cortex at one of two time points: (1) Prior to fear conditioning, or (2) after conditioning. Delay auditory conditioning was achieved by pairing a tone with a foot shock in "context A". Extinction training involved the presentation of tones in a different context (context B) in the absence of foot shock. Test for extinction memory was achieved by presentation of additional tones alone in context B over the following two days. In pre- or post-injury paradigms, CCI did not influence fear learning and extinction. Furthermore, CCI did not affect locomotor activity or elevated plus maze testing. Our results demonstrate that, within the time frame studied, CCI does not impair the acquisition and expression of conditioned fear or extinction memory.
| S-EPMC4518729 | biostudies-literature
Project description:RationaleEpigenetic and/or genetic variation in the gene encoding the receptor for adenylate-cyclase activating polypeptide 1 (ADCYAP1R1) has been linked to post-traumatic stress disorder in adults and anxiety in children. Psychosocial stress has been linked to asthma morbidity in Puerto Rican children.ObjectivesTo examine whether epigenetic or genetic variation in ADCYAP1R1 is associated with childhood asthma in Puerto Ricans.MethodsWe conducted a case-control study of 516 children ages 6-14 years living in San Juan, Puerto Rico. We assessed methylation at a CpG site in the promoter of ADCYAP1R1 (cg11218385) using a pyrosequencing assay in DNA from white blood cells. We tested whether cg11218385 methylation (range, 0.4-6.1%) is associated with asthma using logistic regression. We also examined whether exposure to violence (assessed by the Exposure to Violence [ETV] Scale in children 9 yr and older) is associated with cg11218385 methylation (using linear regression) or asthma (using logistic regression). Logistic regression was used to test for association between a single nucleotide polymorphism in ADCYAP1R1 (rs2267735) and asthma under an additive model. All multivariate models were adjusted for age, sex, household income, and principal components.Measurements and main resultsEACH 1% increment in cg11218385 methylation was associated with increased odds of asthma (adjusted odds ratio, 1.3; 95% confidence interval, 1.0-1.6; P = 0.03). Among children 9 years and older, exposure to violence was associated with cg11218385 methylation. The C allele of single nucleotide polymorphism rs2267735 was significantly associated with increased odds of asthma (adjusted odds ratio, 1.3; 95% confidence interval, 1.02-1.67; P = 0.03).ConclusionsEpigenetic and genetic variants in ADCYAP1R1 are associated with asthma in Puerto Rican children.
| S-EPMC3733434 | biostudies-literature
Project description:The balance between activities of fear neurons and extinction neurons in the basolateral nucleus of the basal amygdala (BAL) has been hypothesized to encode fear states after extinction. However, it remains unclear whether these neurons are solely responsible for encoding fear states. In this study, we stably recorded single-unit activities in the BAL during fear conditioning and extinction for 3 days, providing a comprehensive view on how different BAL neurons respond during fear learning. We found BAL neurons that showed excitatory responses to the conditioned stimulus (CS) after fear conditioning ('conditioning-potentiated neurons') and another population that showed excitatory responses to the CS after extinction ('extinction-potentiated neurons'). Interestingly, we also found BAL neurons that developed inhibitory responses to the CS after fear conditioning ('conditioning-inhibited neurons') or after extinction ('extinction-inhibited neurons'). BAL neurons that showed excitatory responses to the CS displayed various functional connectivity with each other, whereas less connectivity was observed among neurons with inhibitory responses to the CS. Intriguingly, we found correlative neuronal activities between conditioning-potentiated neurons and neurons with inhibitory responses to the CS. Our findings suggest that distinct BAL neurons, which are responsive to the CS with excitation or inhibition, encode various facets of fear conditioning and extinction.
| S-EPMC8159982 | biostudies-literature
Project description:BackgroundRisk for posttraumatic stress disorder (PTSD) is thought to be mediated by gene × environment (G × E) interactions that affect core cognitive processes such as fear learning. The catechol-O-methyltransferase (COMT) val158met polymorphism has been associated with risk for PTSD and impaired fear inhibition. We used a large, relatively homogenous population to (1) replicate previous findings of poor fear inhibition in COMT Met/Met carriers with PTSD; (2) determine if COMT association with fear inhibition is moderated by childhood trauma (CT), an environmental risk factor for PTSD; and (3) determine if COMT is associated with altered fear processes after recent exposure to combat trauma.MethodsMale Marines and Navy Corpsmen of European-American ancestry were assessed prior to (n = 714) and 4-6 months after deployment to Afghanistan (n = 452). Acquisition and extinction of fear-potentiated startle, childhood and combat trauma history, and PTSD diagnosis were assessed at both time points.ResultsBefore deployment, Met/Met genotype was associated with fear inhibition deficits in participants with current PTSD; however, this association was dependent on CT exposure. After deployment, combat trauma was associated with a modest reduction in fear extinction in Met/Met compared with Val/Val carriers. There were no associations of COMT genotype with fear extinction within healthy and non-traumatized individuals.ConclusionsThese findings support the hypothesis that G × E interactions underlie associations of COMT val158met with fear inhibition deficits. These studies confirm that Met/Met carriers with PTSD have poor fear inhibition, and support further research in understanding how this polymorphism might impact response to extinction-based therapies.
| S-EPMC5760328 | biostudies-literature
Project description:Exposure to childhood trauma is extremely common (>60 %) and is a leading risk factor for fear-based disorders, including anxiety and posttraumatic stress disorder. These disorders are characterized by deficits in fear extinction and dysfunction in underlying neural circuitry. Given the strong and pervasive link between childhood trauma and the development of psychopathology, fear extinction may be a key mechanism. The present study tests the impact of childhood trauma exposure on fear extinction and underlying neural circuitry. Children (N = 44, 45 % trauma-exposed; 6-11 yrs) completed a novel two-day virtual reality fear extinction experiment. On day one, participants underwent fear conditioning and extinction. Twenty-four hours later, participants completed a test of extinction recall during fMRI. Conditioned fear was measured throughout the experiment using skin conductance and fear-related behavior, and activation in fear-related brain regions was estimated during recall. There were no group differences in conditioned fear during fear conditioning or extinction learning. During extinction recall, however, trauma-exposed children kept more distance from both the previously extinguished and the safety cue, suggesting poor differentiation between threat and safety cues. Trauma-exposed youth also failed to approach the previously extinguished cue over the course of extinction recall. The effects on fear-related behavior during extinction recall were accompanied by higher activation to the previously extinguished cue in fear-relevant brain regions, including the dorsal anterior cingulate cortex and anterior insula, in trauma-exposed relative to control children. Alterations in fear-related brain regions and fear-related behavior may be a core mechanism through which childhood trauma confers heightened vulnerability to psychopathology.
| S-EPMC7722124 | biostudies-literature
Project description:A fundamental question in neuroscience is how memories are stored and retrieved in the brain. Many neurological, psychiatric and neurodevelopmental disorders are associated with cognitive deficits. Therefore characterizing the biological basis of these processes is critical for understanding normal and abnormal brain function. It is known that long-term memory formation requires transcription and translation as well as epigenetic processes that control gene expression. In this study we examined genome-wide gene expression changes during memory consolidation and after memory retrieval. We observe the largest changes in gene expression 30 minutes after memory acquisition and retrieval, and several novel genes were found to be affected by both. Interestingly, acquisition and retrieval of memory down-regulate different processes. Chromatin assembly is down-regulated after memory acquisition whereas RNA processing is down-regulated so after retrieval. Histone variant H2AB levels are reduced following acquisition, while splicing factor Rbfox1 and NMDA receptor-dependent microRNA miR-219 are down-regulated following retrieval. We also show that miR-219 down-regulation after retrieval is accompanied by up-regulation of its target protein CAMKIIγ. Our study highlights for the first time the differential involvement of epigenetic mechanisms that control gene expression, such as histone variants and post-transcriptional RNA processing, during memory acquisition and retrieval.
2014-10-02 | GSE50423 | GEO