Endocannabinoids and the development of extinction recall neural circuitry in adolescents

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PROJECT SUMMARY/ABSTRACT Anxiety disorders are characterized by a failure to appropriately inhibit or extinguish fear. Successful extinction learning, and its later recall depend on hippocampal (HPC)-ventromedial prefrontal cortex (vmPFC) circuitry, and adults with posttraumatic stress disorder (PTSD) show decreased activation and connectivity between these regions and poor extinction recall. Growing research establishes the key role of the endocannabinoid (eCB) system in modulating fear extinction and underlying HPC-vmPFC circuitry, making the eCB system a novel mechanistic and therapeutic target for anxiety disorders. Emerging data from animal models suggest that eCB signaling peaks and falls sharply during early adolescence and then stabilizes in late adolescence as individuals approach young adulthood, which corresponds with the emergence of anxiety disorders. However, there is limited evidence of how eCB signaling changes in humans across adolescence, and potential links between eCB signaling and extinction recall and underlying HPC-vmPFC circuitry. The goal of this training project is for PI Marusak to develop conceptual and methodological expertise, and an independent scientific research program, to evaluate in adolescents the novel hypotheses that: (1) fear extinction recall ability increases across adolescence, (2) age-related increases in extinction recall correspond with increased activation of HPC-vmPFC circuitry, and (3) higher blood levels of the eCB anandamide (AEA) correspond with better extinction recall and/or higher activation within HPC-vmPFC circuitry among adolescents. Engaging in this protected training time will allow the PI to develop an innovative, translational program of research focused on adolescent anxiety that fills a unique niche by bridging her background and training in neural development, childhood adversity, and neuroimaging with emerging expertise in 4 new areas: (1) translational research on fear and fear-related pathology, (2) cannabinoid neurobiology and pharmacology, (3) clinical trials design and statistical analysis, and (4) career development. The research and training plan take advantage of the breadth and expertise of the mentorship team in fear conditioning and extinction, anxiety disorders, and novel eCB treatments in adults (Mentor Rabinak), trauma, anxiety disorders, and fear conditioning and extinction, in children, adolescents, and adults (Co-Mentor Jovanovic), human pharmacology, affect, and substance use disorders (Co-Mentor Greenwald), and molecular neurobiology and animal models of fear-based learning (Co- Mentor Lee). Co-Mentor Ghosh is a biostatistician with expertise in clinical trials design and statistical analysis. Together with the rich environment of Wayne State University, this Award will provide the focused training and pilot data needed for a productive independent career dedicated to advancing our understanding of neurodevelopmental mechanisms leading to anxiety disorders, and to using that knowledge to develop more effective interventions to circumvent the development of anxiety in at-risk youth (e.g., lower income, exposed to adversity).