OBJECTIVE: Many studies have shown that 5-HTTLPR genotype interacts with exposure to stress in conferring risk for psychopathology. However, the specific neural mechanisms through which this gene-by-environment interaction confers risk remain largely unknown, and no study to date has directly examined the modulatory effects of 5-HTTLPR on corticolimbic circuit responses during exposure to acute stress. METHOD: An acute laboratory stressor was administered to 51 healthy women during blood-oxygen-level-dependent functional magnetic resonance imaging. In this task, participants were threatened with electric shocks of uncertain intensity, which were unpredictably delivered to the wrist after a long anticipatory cue period of unpredictable duration. RESULTS: Relative to women carrying the L allele, those with the SS genotype showed enhanced activation during threat anticipation in a network of regions, including the amygdala, hippocampus, anterior insula, thalamus, pulvinar, caudate, precuneus, anterior cingulate cortex, and medial prefrontal cortex. Individuals with the SS genotype also displayed enhanced positive coupling between medial prefrontal cortex activation and anxiety experience, whereas enhanced negative coupling between insula activation and perceived success at regulating anxiety was observed in individuals carrying the L allele. CONCLUSIONS: These findings suggest that during stress exposure, neural systems that enhance fear and arousal, modulate attention toward threat, and perseverate on emotional salience of the threat may be engaged preferentially in individuals with the SS genotype. This may be one mechanism underlying the risk for psychopathology conferred by the S allele upon exposure to life stressors.
The patterns of comorbidity among prevalent mental disorders in adults lead them to load on ``externalizing,'' ``distress,'' and ``fears'' factors. These factors are themselves robustly correlated, but little attention has been paid to this fact. As a first step in studying the implications of these interfactor correlations, we conducted confirmatory factor analyses on diagnoses of 11 prevalent Diagnostic and Statistical Manual of Mental Disorders (4th ed.) mental disorders in a nationally representative sample. A model specifying correlated externalizing, distress, and fears factors fit well, but an alternative model was tested in which a ``general'' bifactor was added to capture what these disorders share in common. There was a modest but significant improvement in fit for the bifactor model relative to the 3-factor oblique model, with all disorders loading strongly on the bifactor. Tests of external validity revealed that the fears, distress, and externalizing factors were differentially associated with measures of functioning and potential risk factors. Nonetheless, the general bifactor accounted for significant independent variance in future psychopathology, functioning, and other criteria over and above the fears, distress, and externalizing factors. These findings support the hypothesis that these prevalent forms of psychopathology have both important common and unique features. Future studies should determine whether this is because they share elements of their etiology and neurobiological mechanisms. If so, the existence of common features across diverse forms of prevalent psychopathology could have important implications for understanding the nature, etiology, and outcomes of psychopathology. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
Endocannabinoids are released 'on-demand' on the basis of physiological need, and can be pharmacologically augmented by inhibiting their catabolic degradation. The endocannabinoid anandamide is degraded by the catabolic enzyme fatty acid amide hydrolase (FAAH). Anandamide is implicated in the mediation of fear behaviors, including fear extinction, suggesting that selectively elevating brain anandamide could modulate plastic changes in fear. Here we first tested this hypothesis with preclinical experiments employing a novel, potent and selective FAAH inhibitor, AM3506 (5-(4-hydroxyphenyl)pentanesulfonyl fluoride). Systemic AM3506 administration before extinction decreased fear during a retrieval test in a mouse model of impaired extinction. AM3506 had no effects on fear in the absence of extinction training, or on various non-fear-related measures. Anandamide levels in the basolateral amygdala were increased by extinction training and augmented by systemic AM3506, whereas application of AM3506 to amygdala slices promoted long-term depression of inhibitory transmission, a form of synaptic plasticity linked to extinction. Further supporting the amygdala as effect-locus, the fear-reducing effects of systemic AM3506 were blocked by intra-amygdala infusion of a CB1 receptor antagonist and were fully recapitulated by intra-amygdala infusion of AM3506. On the basis of these preclinical findings, we hypothesized that variation in the human FAAH gene would predict individual differences in amygdala threat-processing and stress-coping traits. Consistent with this, carriers of a low-expressing FAAH variant (385A allele; rs324420) exhibited quicker habituation of amygdala reactivity to threat, and had lower scores on the personality trait of stress-reactivity. Our findings show that augmenting amygdala anandamide enables extinction-driven reductions in fear in mouse and may promote stress-coping in humans.Molecular Psychiatry advance online publication, 12 June 2012; doi:10.1038/mp.2012.72.
BACKGROUND: Stressful life events are among the most reliable precipitants of major depressive disorder; yet, not everyone exposed to stress develops depression. It has been hypothesized that robust neural reactivity to reward and associated stable levels of positive affect (PA) may protect against major depressive disorder in the context of environmental adversity. However, little empirical data exist to confirm this postulation. Here, we test the hypothesis that individuals with relatively low ventral striatum (VS) reactivity to reward will show low PA levels in the context of recent life stress, while those with relatively high VS reactivity will be protected against these potentially depressogenic effects. METHODS: Differential VS reactivity to positive feedback was assessed using blood oxygen level-dependent functional magnetic resonance imaging in a sample of 200 nonpatient young adults. Recent life stress, current depressive symptoms, and PA were assessed via self-report. Linear regression models were used to investigate the moderating effects of VS reactivity on the relationship between recent stress and state PA across participants. RESULTS: Recent life stress interacted with VS reactivity to predict self-reported state PA, such that higher levels of life stress were associated with lower PA for participants with relatively low, but not for those with high, VS reactivity. These effects were independent of age, gender, race/ethnicity, trait PA, and early childhood trauma. CONCLUSIONS: The current results provide empirical evidence for the potentially protective role of robust reward-related neural responsiveness against reductions in PA that may occur in the wake of life stress and possibly vulnerability to depression precipitated by stressful life events.
BACKGROUND: Striking parallels are observed when comparing the literature on the 5-HTTLPR of the serotonin transporter gene (SLC6A4) to the testosterone (T) literature on measures of stress reactivity and neural activity. Short (S) allele carriers and individuals higher in testosterone levels show exaggerated stress responses, amygdala hyperactivity, and reduction of amygdala-prefrontal cortex coupling when exposed to threat. METHODS: Three studies tested the hypothesis that higher T, S carriers would show increased cortisol responses to threat. RESULTS: Supporting the hypothesis, a T x 5-HTTLPR interaction was obtained across all studies. Threats to status via social exclusion (Study 1), cognitive/perceptual failure (Study 2), and physical competence (Study 3) all produced elevated cortisol levels in S carriers with higher T levels. An unexpected result was that 5-HTTLPR long (L) allele homozygotes with higher T showed lower cortisol levels in response to threat-a pattern of response that closely parallels that reported for psychopathic individuals. Finally, combining effect sizes across studies showed that the likelihood that these effects were due to Type 1 errors was quite low. CONCLUSIONS: What emerges from these studies is a novel yet reliable, and synergistic relationship between 5-HTTLPR genotype and testosterone on stress reactivity, possibly conferring vulnerability for multiple neuropsychiatric disorders.