Endocannabinoids, stress response, and prefrontal engagement during emotion regulation in adolescent suicidal ideation - PROJECT SUMMARY Suicide is a critical public health concern, particularly among adolescents, where it ranks as the second- leading cause of death. Suicidal ideation (SI), which peaks in late adolescence, typically precedes suicide attempts and strongly predicts suicide risk. Mitigating this risk in adolescents is challenging, as many fail to disclose SI and current treatments do not fully address SI-related concerns. Furthermore, SI can be precipitated by psychosocial stress, which becomes more prevalent during adolescence, and may be exacerbated by difficulties regulating emotional responses to stress. Emerging research suggests that the endocannabinoid (eCB) system, which plays a critical role in regulating stress and emotional responses, may be altered in adults at risk for suicide. However, the role of the eCB system in adolescent suicide risk remains underexplored. The proposed study aims to address this gap by comparing eCB system function at rest and in response to stress in adolescents (ages 14-17 years) with and without SI, and link circulating eCBs to prefrontal emotion regulation processes in the SI group. It is hypothesized that adolescents with SI will exhibit higher resting eCB concentrations but a blunted eCB response to acute psychosocial stress compared with controls. Further, it is predicted that eCB system alterations will be linked to greater dorsolateral prefrontal cortex (dlPFC) engagement during cognitive reappraisal, an area and form of emotion regulation associated with dysfunction in youth with SI. To test these hypotheses, 30 adolescents with SI and moderate depressive symptoms and 30 matched controls without SI (matched for depressive symptoms, age, and sex) will be recruited to this two-day study. On the first day, participants will complete the Trier Social Stress Test (a psychosocial stressor), with blood samples collected before and after the task. The following day, adolescents will complete a cognitive reappraisal task during functional neuroimaging to assess dlPFC engagement. Complementary data, including psychiatric symptoms, related lipids, and additional task-based and resting- state fMRI data will be collected. This research will elucidate the role of the eCB system as it relates to stress and emotion regulation in adolescents with SI, which may contribute to improvements in risk detection and treatments. The mentorship team, consisting of experts in adolescent SI, pediatric neuroimaging, child/adolescent psychiatry, biostatistics, and eCBs, is uniquely positioned to guide PI Ely in this project. The proposed training and research plan will provide PI Ely with the knowledge and skills that are critical for her to expand this work into a postdoctoral research fellowship, supporting her goal of developing an independent research career focused on improving SI risk detection and treatments in adolescents.
