Learning from other people's fear: amygdala-based social reference learning in social anxiety disorder

Background Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood. Methods We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety, and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice. Results Selective 2-AG augmentation reduced anxiety in the light-dark box assay, and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct CB1 receptor stimulation with tetrahydrocannabinol (THC). Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation. Conclusions Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than previously appreciated.

Instructions, suggestions, and other types of social information can have powerful effects on pain and emotion. Prominent examples include observational learning, social influence, placebo, and hypnosis. These different phenomena and their underlying brain mechanisms have been studied in partially separate literatures, which we discuss, compare, and integrate in this review. Converging findings from these literatures suggest that 1) instructions and social information affect brain systems associated with the generation of pain and emotion, and with reinforcement learning, and that 2) these changes are mediated by alterations in prefrontal systems responsible for top-down control and the generation of affective meaning. We argue that changes in expectation and appraisal, a process of assessing personal meaning and implications for wellbeing, are two potential key mediators of the effects of instructions and social information on affective experience. Finally, we propose a tentative model of how prefrontal regions, especially dorsolateral and ventromedial prefrontal cortex may regulate affective processing based on instructions and socially transmitted expectations more broadly.

Background Generalized anxiety disorder (GAD) can significantly impair quality of life and is associated with a relatively poor long‐term prognosis. Anxiety disorders are often associated with hyper‐responsiveness to threat, perhaps coupled with impaired executive functioning. However, GAD, particularly adolescent GAD, has been the focus of little functional neuroimaging work compared to other anxiety disorders. Here, we examine the neural association of adolescent GAD with responsiveness to threat and response control. Methods The study involved 35 adolescents with GAD and 34 healthy comparison individuals (N = 69) matched on age, gender, and IQ. Participants were scanned during an affective number Stroop task. Results We found significant Group‐by‐Task Condition interactions in regions involved in response control/motor responding (bilateral precentral gyri and cerebellum) and/or cognitive control/attention (dorsomedial and lateral frontal cortex, posterior cingulate cortex, cuneus, and precuneus). In line with predictions, the youth with GAD showed significantly less recruitment during task trials than the healthy comparison individuals. However, no indications of specific heightened responses to threat were seen. Conclusions GAD involves reduced capacity for engaging regions involved in response control/motor responding and/or cognitive control/attention. This might reflect either a secondary consequence of the patient's worry or an early risk factor for the development of worry.