Fear Inhibition in High Trait Anxiety

Trait anxiety is recognized as an individual risk factor for the development of anxiety disorders but the neurobiological mechanisms remain unknown. Here we test whether trait anxiety is associated with impaired fear inhibition utilizing the AX+/BX- conditional discrimination procedure that allows for the independent evaluation of startle fear potentiation and inhibition of fear [1]. Sixty undergraduate students participated in the study - High Trait Anxious: n = 28 and Low Trait Anxious: n = 32. We replicated earlier findings that a transfer of conditioned inhibition for startle responses requires contingency awareness. However, contrary to the fear inhibition hypothesis, our data suggest that high trait anxious individuals show a normal fear inhibition of conditioned startle responding. Only at the cognitive level the high trait anxious individuals showed evidence for impaired inhibitory learning of the threat cue. Together with other findings where impaired fear inhibition was only observed in those PTSD patients who were either high on hyperarousal symptoms [2] or with current anxiety symptoms [3], we question whether impaired fear inhibition is a biomarker for the development of anxiety disorders.     

Epigenetic Priming of Memory Updating during Reconsolidation to Attenuate Remote Fear Memories

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Unconditioned Stimulus Revaluation to Promote Conditioned Fear Extinction in the Memory Reconsolidation Window

The retrieval-extinction paradigm, which disrupts the reconsolidation of fear memories in humans, is a non-invasive technique that can be used to prevent the return of fear in humans. In the present study, unconditioned stimulus revaluation was applied in the retrieval-extinction paradigm to investigate its promotion of conditioned fear extinction in the memory reconsolidation window after participants acquired conditioned fear. This experiment comprised three stages (acquisition, unconditioned stimulus revaluation, retrieval-extinction) and three methods for indexing fear (unconditioned stimulus expectancy, skin conductance response, conditioned stimulus pleasure rating). After the acquisition phase, we decreased the intensity of the unconditioned stimulus in one group (devaluation) and maintained constant for the other group (control). The results indicated that both groups exhibited similar levels of unconditioned stimulus expectancy, but the devaluation group had significantly smaller skin conductance responses and exhibited a growth in conditioned stimulus + pleasure. Thus, our findings indicate unconditioned stimulus revaluation effectively promoted the extinction of conditioned fear within the memory reconsolidation window.     

Impact of Working Memory Load on Cognitive Control in Trait Anxiety: An ERP Study

Whether trait anxiety is associated with a general impairment of cognitive control is a matter of debate. This study investigated whether and how experimentally manipulated working memory (WM) load modulates the relation between trait anxiety and cognitive control. This question was investigated using a dual-task design in combination with event-related potentials. Participants were required to remember either one (low WM load) or six letters (high WM load) while performing a flanker task. Our results showed that a high WM load disrupted participants'' ability to overcome distractor interference and this effect was exacerbated for the high trait-anxious (HTA) group. This exacerbation was reflected by larger interference effects (i.e., incongruent minus congruent) on reaction times (RTs) and N2 amplitudes for the HTA group than for the low trait-anxious group under high WM load. The two groups, however, did not differ in their ability to inhibit task-irrelevant distractors under low WM load, as indicated by both RTs and N2 amplitudes. These findings underscore the significance of WM-related cognitive demand in contributing to the presence (or absence) of a general cognitive control deficit in trait anxiety. Furthermore, our findings show that when limited WM resources are depleted by high WM load, HTA individuals exhibit less efficient recruitments of cognitive control required for the inhibition of distractors, therefore resulting in a greater degree of response conflict.     

A Key Role for Nectin-1 in the Ventral Hippocampus in Contextual Fear Memory

Nectins are cell adhesion molecules that are widely expressed in the brain. Nectin expression shows a dynamic spatiotemporal regulation, playing a role in neural migratory processes during development. Nectin-1 and nectin-3 and their heterophilic trans-interactions are important for the proper formation of synapses. In the hippocampus, nectin-1 and nectin-3 localize at puncta adherentia junctions and may play a role in synaptic plasticity, a mechanism essential for memory and learning. We evaluated the potential involvement of nectin-1 and nectin-3 in memory consolidation using an emotional learning paradigm. Rats trained for contextual fear conditioning showed transient nectin-1—but not nectin-3—protein upregulation in synapse-enriched hippocampal fractions at about 2 h posttraining. The upregulation of nectin-1 was found exclusively in the ventral hippocampus and was apparent in the synaptoneurosomal fraction. This upregulation was induced by contextual fear conditioning but not by exposure to context or shock alone. When an antibody against nectin-1, R165, was infused in the ventral-hippocampus immediately after training, contextual fear memory was impaired. However, treatment with the antibody in the dorsal hippocampus had no effect in contextual fear memory formation. Similarly, treatment with the antibody in the ventral hippocampus did not interfere with acoustic memory formation. Further control experiments indicated that the effects of ventral hippocampal infusion of the nectin-1 antibody in contextual fear memory cannot be ascribed to memory non-specific effects such as changes in anxiety-like behavior or locomotor behavior. Therefore, we conclude that nectin-1 recruitment to the perisynaptic environment in the ventral hippocampus plays an important role in the formation of contextual fear memories. Our results suggest that these mechanisms could be involved in the connection of emotional and contextual information processed in the amygdala and dorsal hippocampus, respectively, thus opening new venues for the development of treatments to psychopathological alterations linked to impaired contextualization of emotions.     

A Novel Form of Memory for Auditory Fear Conditioning at a Low-Intensity Unconditioned Stimulus

Fear is one of the most potent emotional experiences and is an adaptive component of response to potentially threatening stimuli. On the other hand, too much or inappropriate fear accounts for many common psychiatric problems. Cumulative evidence suggests that the amygdala plays a central role in the acquisition, storage and expression of fear memory. Here, we developed an inducible striatal neuron ablation system in transgenic mice. The ablation of striatal neurons in the adult brain hardly affected the auditory fear learning under the standard condition in agreement with previous studies. When conditioned with a low-intensity unconditioned stimulus, however, the formation of long-term fear memory but not short-tem memory was impaired in striatal neuron-ablated mice. Consistently, the ablation of striatal neurons 24 h after conditioning with the low-intensity unconditioned stimulus, when the long-term fear memory was formed, diminished the retention of the long-term memory. Our results reveal a novel form of the auditory fear memory depending on striatal neurons at the low-intensity unconditioned stimulus.     

Identification of a Functional Connectome for Long-Term Fear Memory in Mice

Long-term memories are thought to depend upon the coordinated activation of a broad network of cortical and subcortical brain regions. However, the distributed nature of this representation has made it challenging to define the neural elements of the memory trace, and lesion and electrophysiological approaches provide only a narrow window into what is appreciated a much more global network. Here we used a global mapping approach to identify networks of brain regions activated following recall of long-term fear memories in mice. Analysis of Fos expression across 84 brain regions allowed us to identify regions that were co-active following memory recall. These analyses revealed that the functional organization of long-term fear memories depends on memory age and is altered in mutant mice that exhibit premature forgetting. Most importantly, these analyses indicate that long-term memory recall engages a network that has a distinct thalamic-hippocampal-cortical signature. This network is concurrently integrated and segregated and therefore has small-world properties, and contains hub-like regions in the prefrontal cortex and thalamus that may play privileged roles in memory expression.     

Wiring and Volume Transmission in Rat Amygdala. Implications for Fear and Anxiety

The amygdala plays a key role in anxiety. Information from the environment reaches the amygdaloid basolateral nucleus and after its processing is relayed to the amygdaloid central nucleus where a proper anxiogenic response is implemented. Experimental evidence indicates that in this information transfer a GABAergic interface controls the trafficking of impulses between the two nuclei. Recent work indicates that interneuronal communication can take place by classical synaptic transmission (wiring transmission) and by volume transmission in which the neurotransmitter diffuses and flows through the extracellular space from its site of release and binds to extrasynaptic receptors at various distances from the source. Based on evidence from our laboratory the concept is introduced that neurotransmitters in the amygdala can modulate anxiety involving changes in fear learning and memories by effects on receptor mosaics in the fear circuits through wiring and volume transmission modes of communication. Special issue article in honor of Dr. Ricardo Tapia.     

Neuroendocrine Response to School Load in Prepubertal Children: Focus on Trait Anxiety

At the time of school-age, the most frequent stress stimuli are related to school environment and educational process. Anxiety may play a big role in coping with stressful situations associated with school load. To approach this issue, we performed a real-life study at school during the classwork. The sample consisted of 36 healthy children aged 10 years, which were divided to low and high trait anxiety group based on the median value of the anxiety score. The investigations were carried out in the classroom during a stress condition (final exams) and non-stress condition (without any exam). In the whole sample, the condition with exam was associated with higher cortisol and lower testosterone concentrations in saliva compared to the condition without exam. The activity of salivary alpha-amylase increased at the end of the exam. Anxious children showed higher concentrations of aldosterone and lower activity of alpha-amylase compared to children with low trait anxiety. Cortisol levels were higher in anxious children in the first morning samples before starting the lessons. Children with high and low trait anxiety did not differ in extraversion, neuroticism, as well as non-verbal intelligence and school success. Thus, the anxious children at school showed a more rapid decrease of anticipatory stress-induced cortisol concentrations, higher aldosterone levels, and lower alpha-amylase activities compared to non-anxious children. These changes, particularly high concentrations of aldosterone in children with high trait anxiety, may have an impact on their psychophysiological development.     

Alligators and Endocrine Disrupting Contaminants: A Current Perspective

Many xenobiotic compounds introduced into the environment byhuman activity have been shown to adversely affect wildlife.Reproductive disorders in wildlife include altered fertility,reduced viability of offspring, impaired hormone secretion oractivity and modified reproductive anatomy. It has been hypothesizedthat many of these alterations in reproductive function aredue to the endocrine disruptive effects of various environmentalcontaminants. The endocrine system exhibits an organizationaleffect on the developing embryo. Thus, a disruption of the normalhormonal signals can permanently modify the organization andfuture function of the reproductive system. We have examinedthe reproductive and developmental endocrinology of severalpopulations of American alligator (Alligator mississippiensis)living in contaminated and reference lakes and used this speciesas a sentinel species in field studies. We have observed thatneonatal and juvenile alligators living in pesticide-contaminatedlakes have altered plasma hormone concentrations, reproductivetract anatomy and hepatic functioning. Experimental studiesexposing developing embryos to various persistent and nonpersistentpesticides, have produced alterations in gonadal steroidogenesis,secondary sex characteristics and gonadal anatomy. These experimentalstudies have begun to provide the causal relationships betweenembryonic pesticide exposure and reproductive abnormalitiesthat have been lacking in pure field studies of wild populations.An understanding of the developmental consequences of endocrinedisruption in wildlife can lead to new indicators of exposureand a better understanding of the most sensitive life stagesand the consequences of exposure during these periods.     

Levels of State and Trait Anxiety in Patients Referred to Ophthalmology by Primary Care Clinicians: A Cross Sectional Study

Purpose

There is a high level of over-referral from primary eye care leading to significant numbers of people without ocular pathology (false positives) being referred to secondary eye care. The present study used a psychometric instrument to determine whether there is a psychological burden on patients due to referral to secondary eye care, and used Rasch analysis to convert the data from an ordinal to an interval scale.

Design

Cross sectional study.

Participants and Controls

322 participants and 80 control participants.

Methods

State (i.e. current) and trait (i.e. propensity to) anxiety were measured in a group of patients referred to a hospital eye department in the UK and in a control group who have had a sight test but were not referred. Response category analysis plus infit and outfit Rasch statistics and person separation indices were used to determine the usefulness of individual items and the response categories. Principal components analysis was used to determine dimensionality.

Main Outcome Measure

Levels of state and trait anxiety measured using the State-Trait Anxiety Inventory.

Results

State anxiety scores were significantly higher in the patients referred to secondary eye care than the controls (p<0.04), but similar for trait anxiety (p>0.1). Rasch analysis highlighted that the questionnaire results needed to be split into “anxiety-absent” and “anxiety-present” items for both state and trait anxiety, but both subscales showed the same profile of results between patients and controls.

Conclusions

State anxiety was shown to be higher in patients referred to secondary eye care than the controls, and at similar levels to people with moderate to high perceived susceptibility to breast cancer. This suggests that referral from primary to secondary eye care can result in a significant psychological burden on some patients.