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.

Background Fatty acid amide hydrolase (FAAH) is a key enzyme in regulating endocannabinoid (eCB) signaling. A common single nucleotide polymorphism (C385A) in the human FAAH gene has been associated with increased risk for addiction and obesity. Methods Using imaging genetics in 82 healthy adult volunteers, we examined the effects of FAAH C385A on threat- and reward-related human brain function. Results Carriers of FAAH 385A, associated with reduced enzyme and, possibly, increased eCB signaling, had decreased threat-related amygdala reactivity but increased reward-related ventral striatal reactivity in comparison to C385 homozygotes. Similar divergent effects of FAAH C385A genotype were manifest at the level of brain-behavior relationships. 385A carriers showed decreased correlation between amygdala reactivity and trait anxiety but increased correlation between ventral striatal reactivity and delay discounting, an index of impulsivity. Conclusions Our results parallel pharmacologic and genetic dissection of eCB signaling, are consistent with the psychotropic effects of Δ9-tetrahydrocannabinol and highlight specific neural mechanisms through which variability in eCB signaling impacts complex behavioral processes related to risk for addiction and obesity.

Background 5-HT1A autoreceptors mediate negative feedback inhibition of serotonergic neurons and play a critical role in regulating 5-HT signaling involved in shaping the functional response of major forebrain targets, such as the amygdala, supporting complex behavioral processes. A common functional variation (C(-1019)G) in the human 5-HT1A gene (HTR1A) represents one potential source of such inter-individual variability. Both in vitro and in vivo the -1019G blocks transcriptional repression leading to increased autoreceptor expression. Thus, the -1019G may contribute to relatively decreased 5-HT signaling at postsynaptic forebrain target sites via increased negative feedback. Objectives & Design To use imaging genetics to evaluate the effects of HTR1A C(-1019)G on amygdala reactivity in 89 healthy adults and employ path analyses to explore the impact of HTR1A-mediated variability in amygdala reactivity on individual differences in trait anxiety. We hypothesized that the -1019G, which potentially results in decreased 5-HT signaling, would be associated with relatively decreased amygdala reactivity and related trait anxiety. Results Consistent with prior findings, the -1019G was associated with significantly decreased threat-related amygdala reactivity. Importantly, this effect was independent of that associated with another common functional polymorphism impacting 5-HT signaling, namely the 5-HTTLPR. While there were no direct genotype effects on trait anxiety, the HTR1A C(-1019)G indirectly predicted 9.2% of interindividual variability in trait anxiety through its effects on amygdala reactivity. Conclusions Our findings further implicate relatively increased 5-HT signaling, associated with genetic variation mediating increased 5-HT1A autoreceptors, in driving amygdala reactivity and trait anxiety. Moreover, they provide empirical documentation of the basic premise that genetic variation impacts emergent behavioral processes related to psychiatric disease risk indirectly by biasing the response of underlying neural circuitries.

Several lines of research have illustrated that negative environments can precipitate psychopathology, particularly in the context of relatively increased biological risk, while social resources can buffer the effects of these environments. However, little research has examined how social resources might buffer proximal biological risk for psychopathology or the neurobiological pathways through which such buffering may be mediated. Here we report that the expression of trait anxiety as a function of threat-related amygdala reactivity is moderated by perceived social support, a resource for coping with adversity. A significant positive correlation between amygdala reactivity and trait anxiety was evident in individuals reporting below-average levels of support but not in those reporting average or above-average levels. These results were consistent across multiple measures of trait anxiety and were specific to anxiety in that they did not extend to measures of broad negative or positive affect. Our findings illuminate a biological pathway, namely moderation of amygdala-related anxiety, through which social support may confer resilience to psychopathology. Moreover, our results indicate that links between neural reactivity and behavior are not static but rather may be contingent on social resources.

BackgroundThe experience of early life stress is a consistently identified risk factor for the development of mood and anxiety disorders. Preclinical research employing animal models of early life stress has made inroads in understanding this association and suggests that the negative sequelae of early life stress may be mediated by developmental disruption of corticolimbic structures supporting stress responsiveness. Work in humans has corroborated this idea, as childhood adversity has been associated with alterations in gray matter volumes of the hippocampus, amygdala, and medial prefrontal cortex. Yet, missing from this body of research is a full understanding of how these neurobiological vulnerabilities may mechanistically contribute to the reported link between adverse childhood experiences and later affective psychopathology.ResultsAnalyses revealed that self-reported childhood maltreatment was associated with reduced gray matter volumes within the medial prefrontal cortex and left hippocampus. Furthermore, reduced left hippocampal and medial prefrontal gray matter volume mediated the relationship between childhood maltreatment and trait anxiety. Additionally, individual differences in corticolimbic gray matter volume within these same structures predicted the anxious symptoms as a function of life stress 1 year after initial assessment.ConclusionsCollectively, these findings provide novel evidence that reductions in corticolimbic gray matter, particularly within the hippocampus and medial prefrontal cortex, are associated with reported childhood maltreatment and individual differences in adult trait anxiety. Furthermore, our results suggest that these structural alterations contribute to increased affective sensitivity to stress later in life in those that have experienced early adversity. More broadly, the findings contribute to an emerging literature highlighting the critical importance of early stress on the development of corticolimbic structures supporting adaptive functioning later in life.

SUMMARY In studies employing functional magnetic resonance imaging (fMRI), reactivity of the amygdala to threat-related sensory cues (viz., facial displays of negative emotion) has been found to correlate positively with interindividual variability in testosterone levels of women and young men and to increase on acute administration of exogenous testosterone. Many of the biological actions of testosterone are mediated by intracellular androgen receptors (ARs), which exert transcriptional control of androgen-dependent genes and are expressed in various regions of the brain, including the amygdala. Transactivation potential of the AR decreases (yielding relative androgen insensitivity) with expansion a polyglutamine stretch in the N-terminal domain of the AR protein, as encoded by a trinucleotide (CAG) repeat polymorphism in exon 1 of the X-chromosome AR gene. Here we examined whether amygdala reactivity to threat-related facial expressions (fear, anger) differs as a function of AR CAG length variation and endogenous (salivary) testosterone in a mid-life sample of 41 healthy men (mean age = 45.6 yr, range: 34–54 yr; CAG repeats, range: 19–29). Testosterone correlated inversely with participant age (r = −0.39, p = 0.012) and positively with number of CAG repeats (r = 0.45, p = 0.003). In partial correlations adjusted for testosterone level, reactivity in the ventral amygdala was lowest among men with largest number of CAG repeats. This inverse association was seen in both the right (rp = −0.34, p<0.05) and left (rp = −0.32, p<0.05) hemisphere. Activation of dorsal amygdala, correlated positively with individual differences in salivary testosterone, also in right (r = 0.40, p<0.02) and left (r = 0.32, p<0.05) hemisphere, but was not affected by number of CAG repeats. Hence, androgenic influences on threat-related reactivity in the ventral amygdala may be moderated partially by CAG length variation in the AR gene. Because individual differences in salivary testosterone also predicted dorsal amygdala reactivity and did so independently of CAG repeats, it is suggested that androgenic influences within this anatomically distinct region may be mediated, in part, by non-genomic or AR-independent mechanisms.

The central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST), two nuclei within the central extended amygdala, function as critical relays within the distributed neural networks that coordinate sensory, emotional, and cognitive responses to threat. These structures have overlapping anatomical projections to downstream targets that initiate defensive responses. Despite these commonalities, researchers have also proposed a functional dissociation between the CeA and BNST, with the CeA promoting responses to discrete stimuli and the BNST promoting responses to diffuse threat. Intrinsic functional connectivity (iFC) provides a means to investigate the functional architecture of the brain, unbiased by task demands. Using ultra-high field neuroimaging (7-Tesla fMRI), which provides increased spatial resolution, this study compared the iFC networks of the CeA and BNST in 27 healthy individuals. Both structures were coupled with areas of the medial prefrontal cortex, hippocampus, thalamus, and periaqueductal gray matter. Compared to the BNST, the bilateral CeA was more strongly coupled with the insula and regions that support sensory processing, including thalamus and fusiform gyrus. In contrast, the bilateral BNST was more strongly coupled with regions involved in cognitive and motivational processes, including the dorsal paracingulate gyrus, posterior cingulate cortex, and striatum. Collectively, these findings suggest that responses to sensory stimulation are preferentially coordinated by the CeA and cognitive and motivational responses are preferentially coordinated by the BNST.

In this work, NH2CH=NH2PbI3 (FAPbI3) was employed for light harvesting in inverted planer perovskite solar cells for the first time. Except for the silver cathode, all layers were solution-processed under or below 140 °C. The effect of the annealing process on device performance was investigated. The FAPbI3 solar cells based on a slowed-down annealing shows superior performance compared to the CH3NH3PbI3 (MAPbI3)-based devices, especially for the short circuit current density. A power conversion efficiency of 13.56% was obtained with high short circuit current density of 21.48 mA cm(-2). This work paves the way for low-temperature fabrication of efficient inverted planer structure FAPbI3 perovskite solar cells.