Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces

A distributed, serotonergically innervated neural system comprising extrastriate cortex, amygdala and ventral prefrontal cortex is critical for identification of socially relevant emotive stimuli. The extent to which a genetic variation of serotonin transporter gene 5-HTTLPR impacts functional connectivity between the amygdala and the other components of this neural system remains little examined. In our study, neural activity was measured using event-related functional magnetic resonance imaging in 29 right-handed, white Caucasian healthy subjects as they viewed mild or prototypical fearful and neutral facial expressions. 5-HTTLPR genotype was classified as homozygous for the short allele ( S/S ), homozygous for the long allele ( L/L ) or heterozygous ( S/L ). S/S showed greater activity than L/L within right fusiform gyrus (FG) to prototypically fearful faces. To these fearful faces, S/S more than other genotype subgroups showed significantly greater positive functional connectivity between right amygdala and FG and between right FG and right ventrolateral prefrontal cortex (VLPFC). There was a positive association between measure of psychoticism and degree of functional connectivity between right FG and right VLPFC in response to prototypically fearful faces. Our data are the first to show that genotypic variation in 5-HTTLPR modulates both the amplitude within and the functional connectivity between different components of the visual object-processing neural system to emotionally salient stimuli. These effects may underlie the vulnerability to mood and anxiety disorders potentially triggered by socially salient, emotional cues in individuals with the S allele of 5-HTTLPR.     

Neurochemical analysis of the amygdala basolateral nucleus of rats during anxiety tests

Chlordiazepoxid, phenibut, indoter, campiron, campironin, when administered into the amygdala, improve the anxiety condition of rats in avoidance tests and resemble by their effects dophamine, GABA, or serotonin. Observed differences in the anxiolytic effects between anxiosedative and anxioselective agents seem to be due to an unequal contribution of the monoamin- and aminoacidotergic transmitters into the mechanisms of heteromodal aversive anxiety genesis in the basolateral area of the amygdalar complex.     

Mitophagy in the basolateral amygdala mediates increased anxiety induced by aversive social experience

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Individual differences in the diurnal cortisol response to stress

The objectives of this study were to explore individual differences associated with diverse reactions in cortisol secretion under different stress levels. This study was part of a larger project concerning working hours and health. Thirty-four white-collar workers participated under two different conditions; one work week with a high stress level (H) and one with a lower stress level (L) as measured through self-rated stress during workdays. Based on the morning cortisol concentration during a workday subjects were divided into two groups. One group consisted of subjects whose morning level of cortisol increased in response to the high-stress week, compared to their morning levels in the low-stress condition (Group 1). The other group consisted of subjects whose morning cortisol response was the opposite, with a lower level under the high stress condition (Group 2). Subjects wore actiwatches, completed a sleep diary, and rated their sleepiness and stress for one work week in each condition, i.e., high and low stress. Saliva samples for measures of cortisol were collected on a Wednesday. Group 2 reported higher workload, fatigue, and exhaustion during both weeks. Since there were no differences in perceived stress, neither within nor between groups, the data indicate that there are other factors influencing morning cortisol. The results suggest that one component modulating the cortisol response might be the level of exhaustion, probably related to work overload. Higher levels of stress in exhausted individuals might suppress morning cortisol levels.     

GABAergic circuits of the basolateral amygdala and generation of anxiety after traumatic brain injury

Traumatic brain injury (TBI) has reached epidemic proportions around the world and is a major public health concern in the United States. Approximately 2.8 million individuals sustain a traumatic brain injury and are treated in an Emergency Department yearly in the U.S., and about 50,000 of them die. Persistent symptoms develop in 10–15% of the cases including neuropsychiatric disorders. Anxiety is the second most common neuropsychiatric disorder that develops in those with persistent neuropsychiatric symptoms after TBI. Abnormalities or atrophy in the temporal lobe has been shown in the overwhelming number of TBI cases. The basolateral amygdala (BLA), a temporal lobe structure that consolidates, stores and generates fear and anxiety-based behavioral outputs, is a critical brain region in the anxiety circuitry. In this review, we sought to capture studies that characterized the relationship between human post-traumatic anxiety and structural/functional alterations in the amygdala. We compared the human findings with results obtained with a reproducible mild TBI animal model that demonstrated a direct relationship between the alterations in the BLA and an anxiety-like phenotype. From this analysis, both preliminary insights, and gaps in knowledge, have emerged which may open new directions for the development of rational and more efficacious treatments.

     

Individual differences in impulsivity predict anticipatory eye movements

Impulsivity is the tendency to act without forethought. It is a personality trait commonly used in the diagnosis of many psychiatric diseases. In clinical practice, impulsivity is estimated using written questionnaires. However, answers to questions might be subject to personal biases and misinterpretations. In order to alleviate this problem, eye movements could be used to study differences in decision processes related to impulsivity. Therefore, we investigated correlations between impulsivity scores obtained with a questionnaire in healthy subjects and characteristics of their anticipatory eye movements in a simple smooth pursuit task. Healthy subjects were asked to answer the UPPS questionnaire (Urgency Premeditation Perseverance and Sensation seeking Impulsive Behavior scale), which distinguishes four independent dimensions of impulsivity: Urgency, lack of Premeditation, lack of Perseverance, and Sensation seeking. The same subjects took part in an oculomotor task that consisted of pursuing a target that moved in a predictable direction. This task reliably evoked anticipatory saccades and smooth eye movements. We found that eye movement characteristics such as latency and velocity were significantly correlated with UPPS scores. The specific correlations between distinct UPPS factors and oculomotor anticipation parameters support the validity of the UPPS construct and corroborate neurobiological explanations for impulsivity. We suggest that the oculomotor approach of impulsivity put forth in the present study could help bridge the gap between psychiatry and physiology.     

Individual differences in perceived bitterness predict liking of sweeteners

Although recent molecular studies suggest that only one receptorand one signaling pathway are involved in the perception ofsweetness, this seems to contradict everyday experience thatpeople not only have different likes and dislikes of certainsweeteners but also perceive the sweeteners differently. Onepossible explanation is that variation in liking of sweetenersis due, in part, to variation across individuals in sensitivityto nonsweet tastes, such as bitterness, which are transducedby a variety of receptors. Fifty individuals were asked to rateintensities of several taste attributes of 10 sweeteners andto give hedonic assessments of each sweetener. Additionally,their sensitivity to 6-n-propyl-3-thiouracil (PROP) was determined.Results indicated that when matched for sweetness, the perceptionof bitterness and the sweetener compound were the 2 largestfactors contributing to overall liking of a sweetener. Sensitivityto PROP did not contribute significantly to the model.     

Mechanisms regulating GABAergic inhibitory transmission in the basolateral amygdala: implications for epilepsy and anxiety disorders

Summary. The amygdala, a temporal lobe structure that is part of the limbic system, has long been recognized for its central role in emotions and emotional behavior. Pathophysiological alterations in neuronal excitability in the amygdala are characteristic features of certain psychiatric illnesses, such as anxiety disorders and depressive disorders. Furthermore, neuronal excitability in the amygdala, and, in particular, excitability of the basolateral nucleus of the amygdala (BLA) plays a pivotal role in the pathogenesis and symptomatology of temporal lobe epilepsy. Here, we describe two recently discovered mechanisms regulating neuronal excitability in the BLA, by modulating GABAergic inhibitory transmission. One of these mechanisms involves the regulation of GABA release via kainate receptors containing the GluR5 subunit (GluR5KRs). In the rat BLA, GluR5KRs are present on both somatodendritic regions and presynaptic terminals of GABAergic interneurons, and regulate GABA release in an agonist concentration-dependent, bidirectional manner. The relevance of the GluR5KR function to epilepsy is suggested by the findings that GluR5KR agonists can induce epileptic activity, whereas GluR5KR antagonists can prevent it. Further support for an important role of GluR5KRs in epilepsy comes from the findings that antagonism of GluR5KRs is a primary mechanism underlying the antiepileptic properties of the anticonvulsant topiramate. Another mechanism regulating neuronal excitability in the BLA by modulating GABAergic synaptic transmission is the facilitation of GABA release via presynaptic α_1A adrenergic receptors. This mechanism may significantly underlie the antiepileptic properties of norepinephrine. Notably, the α_1A adrenoceptor-mediated facilitation of GABA release is severely impaired by stress. This stress-induced impairment in the noradrenergic facilitation of GABA release in the BLA may underlie the hyperexcitability of the amygdala in certain stress-related affective disorders, and may explain the stress-induced exacerbation of seizure activity in epileptic patients.     

Individual variability in the stress response of C57BL/6J male mice correlates with trait anxiety

Stress strongly alters the physiology and behavior of some individuals, while others are little or not affected. The causes of this individual variability have remained unknown. Here, we hypothesize that epigenetically induced levels of trait anxiety predict the stress response of individual mice in a genetically homogeneous population. Inbred C57BL/6 male mice were selected for their latency to freely enter from their home cage into an unfamiliar arena and classified as having high or low levels of trait anxiety. Mice were then exposed to acute stress (1-h olfactory contact with a rat) or control conditions. After 24 h, acute stress enhanced state anxiety measured in the elevated-plus maze test only in mice previously classified as having high levels of trait anxiety. This anxiogenic effect of acute stress was paralleled by enhanced novelty-induced plasma corticosterone secretion and increased messenger RNA (mRNA) expression for glucocorticoid and mineralocorticoid receptors in the hippocampus. No effects of acute stress were observed in mice classified as having low levels of trait anxiety. Under unstressed control conditions, mice only differed in basal levels of hippocampal mRNA for the glucocorticoid receptor, which were higher in mice with high trait anxiety than in mice with low trait anxiety. In summary, inbred C57BL/6 mice display a remarkably high interindividual variability in their trait anxiety that predicts the behavioral and neuroendocrine response to an acute stressor, indicating that expression of extremely different coping strategies can develop also between genetically identical individuals.     

Individual differences in the ability to recognise facial identity are associated with social anxiety

Previous research has been concerned with the relationship between social anxiety and the recognition of face expression but the question of whether there is a relationship between social anxiety and the recognition of face identity has been neglected. Here, we report the first evidence that social anxiety is associated with recognition of face identity, across the population range of individual differences in recognition abilities. Results showed poorer face identity recognition (on the Cambridge Face Memory Test) was correlated with a small but significant increase in social anxiety (Social Interaction Anxiety Scale) but not general anxiety (State-Trait Anxiety Inventory). The correlation was also independent of general visual memory (Cambridge Car Memory Test) and IQ. Theoretically, the correlation could arise because correct identification of people, typically achieved via faces, is important for successful social interactions, extending evidence that individuals with clinical-level deficits in face identity recognition (prosopagnosia) often report social stress due to their inability to recognise others. Equally, the relationship could arise if social anxiety causes reduced exposure or attention to people's faces, and thus to poor development of face recognition mechanisms.     

Individual differences in PCA response in the guinea pig

Experiments were carried out to determine the cause of individual differences in the passive cutaneous anaphylaxis (PCA) response in guinea pigs. The intensity of 4-h homologous PCA produced by anti-penicillin G serum was not markedly different among eight reactive sites on the back of a specified animal, whereas considerable individual differences were observed in the PCA response, even at a specified reactive site. PCA was significantly inhibited by an antihistaminic agent, promethazine, and the tissue histamine content was significantly reduced after PCA, suggesting histamine release as a mediator. The intensity of PCA in individual animals was highly correlated with that of the histamine-induced cutaneous reaction elicited at a site adjoining the PCA but was unrelated to skin histamine content. These results suggest that the difference in susceptibility to histamine has a considerable effect on individual differences in the PCA response in guinea pigs.     

Asymmetrical activation in the human brain during processing of fearful faces

Traditional split-field studies and patient research indicate a privileged role for the right hemisphere in emotional processing [1-7], but there has been little direct fMRI evidence for this, despite many studies on emotional-face processing [8-10](see Supplemental Background). With fMRI, we addressed differential hemispheric processing of fearful versus neutral faces by presenting subjects with faces bilaterally [11-13]and orthogonally manipulating whether each hemifield showed a fearful or neutral expression prior to presentation of a checkerboard target. Target discrimination in the left visual field was more accurate after a fearful face was presented there. Event-related fMRI showed right-lateralized brain activations for fearful minus neutral left-hemifield faces in right visual areas, as well as more activity in the right than in the left amygdala. These activations occurred regardless of the type of right-hemifield face shown concurrently, concordant with the behavioral effect. No analogous behavioral or fMRI effects were observed for fearful faces in the right visual field (left hemisphere). The amygdala showed enhanced functional coupling with right-middle and anterior-fusiform areas in the context of a left-hemifield fearful face. These data provide behavioral and fMRI evidence for right-lateralized emotional processing during bilateral stimulation involving enhanced coupling of the amygdala and right-hemispheric extrastriate cortex.     

Individual differences with respect to the sneezing reflex: an inherited physiological trait in man?

Individual differences with respect to the sneezing reflex are described. Visual exposure to strong light may induce a sneezing reaction in about 20% of the individuals in the Swedish population. Preliminary data indicate that the ' sneezer trait' may be inherited in an autosomal dominant fashion. The eventual selective advantage of ST is discussed.     

Individual differences in the cytotoxic T-lymphocyte response in man to public HLA determinants

The allospecific anti-HLA response of cytotoxic T lymphocytes (CTL) from 22 unrelated individuals and 7 monozygous twin pairs was examined. From each responder, CTL were generated in several responder-stimulator combinations, each mismatched for one HLA-A or -B antigen. The CTL were assayed in the cell-mediated lympholysis (CML) on panels of third-party target cells, comprising cells that express the stimulating antigen (specific target cells), cells that express an antigen cross-reactive with the stimulating antigen (CREG target cells), and cells that do not express either the stimulating or a cross-reactive antigen (nonsharing target cells). Individual variations in the allo-CTL response were observed. We identified individuals (responders) who showed a consistently narrow CTL response and those who showed a broad reaction pattern to various stimulator cells. The narrow response was restricted almost entirely to specific target cells; the broad response comprised lysis of specific, CREG, and nonsharing target cells. These differences were evidently not dependent on the HLA-A, -B, -C phenotype of the responder, because HLA-A, -B, (-C)-identical individuals responded differently to the same stimulator. The identical response of monozygous twins indicates that the allogeneic CTL response is genetically controlled. The CTL response is not regulated by the HLA-DR antigens of the responder, nor is it influenced by the DR mismatch between responder and stimulator. The observed differences were not dependent on sex or age and could not be explained by differences in the T-lymphocyte subsets (OKT3+, OKT4+, OKT8+) or by differences in proliferative reactivity to mitogens (phytohemagglutinin, concanavalin A, phorbol-myristate acetate, pokeweed mitogen, anti-T3 monoclonal antibodies). The IL-2 activity in the supernatants of mixed lymphocyte cultures of broad and narrow responder-stimulator combinations did not differ.     

Elevational differences in trait response to UV-B radiation by long-toed salamander populations

Amphibian species capable of optimizing trait response to environmental stressors may develop complex strategies for defending against rapid environmental change. Trait responses may differ between populations, particularly if stressor strength varies across spatial or temporal gradients. Ultraviolet-B (UV-B) radiation is one such stressor that poses a significant threat to amphibian species. We examined the ability of long-toed salamanders (Ambystoma macrodactylum) at high- and low-elevation breeding sites to cooperatively employ behavioral and physiological trait responses to mediate UV-B damage. We performed a microhabitat survey to examine differences in oviposition behavior and UV-B conditions among breeding populations at high- (n = 3; >1,500 m) and low-elevation (n = 3; <100 m) sites. We found significant differences in oviposition behavior across populations, with females at high-elevation sites selecting oviposition substrates in UV-B protected microhabitats. We also collected eggs (n = 633) from each of the breeding sites for analysis of photolyase activity, a photoreactivating enzyme that repairs UV-B damage to the DNA, using a photoproduct immunoassay. Our results revealed no significant differences in photolyase activity between long-toed salamander populations at high and low elevations. For high-elevation salamander populations, relatively low physiological repair capabilities in embryos appear to be buffered by extensive behavioral modifications to reduce UV-B exposure and standardize developmental temperatures. This study provides valuable insight into environmental stress responses via the assessment of multiple traits in allowing sensitive species to persist in rapidly changing landscapes.     

Individual differences in the orienting response: nonresponding in nonclinical samples

The complete failure of the electrodermal orienting response (OR), although widely studied in clinical samples, has received little systematic attention in work with healthy adults. The published studies of nonresponding using nonclinical samples are reviewed, with data from three unpublished studies pertinent to the question, to identify the characteristics of nonresponders. The most durable findings to date are that nonresponding shows both trait and state characteristics, and that nonresponders are more likely to be female than male, to show hypoarousal in the electrodermal system but not complete unresponsiveness in this system or low arousal in other systems, and to show higher scores on measures of impulsiveness and antisociality but not to differ from responders in terms of sensation seeking. Most of these data can be reconciled with two different accounts of the OR mechanism. One is that proposed by I. Maltzman which postulates a difference between voluntary and involuntary ORs, and the other is that of J. A. Gray which proposes that the OR is a function of activity in a Behavioural Inhibition System. Taken together, these accounts imply that the OR reflects attentional and affective processes, and that both cognitive style and temperamental differences in the appraisal of threat can lead to electrodermal nonresponding.     

Glutamatergic synapses from the insular cortex to the basolateral amygdala encode observational pain

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