Abstract 2719 Psychedelic control of neuroimmune interactions governing fear

Introduction: Interactions between the immune system and brain control many aspects of tissue physiology including responses to psychological stress, which affect both immune cell and neural activity.Repeated exposure to psychological stress is a risk factor for developing neuropsychiatric diseases such as major depressive disorder.Still, the interactions between hematopoietic and brain-resident cells that influence behavioral responses to psychological stress are poorly understood.Methods: Here, we used a combination of genomics and CRISPR/Cas9-based behavioral screens to demonstrate that astrocytes in the amygdala limit stress-induced fear behavior through EGFR.Mechanistically, astrocyte EGFR expression inhibits a stress-induced NF-kB signal transduction cascade that increases PTPRS expression in astrocytes.PTPRS signals to Slitrk2-expressing neurons to trigger excitatory synapsestabilizing transcriptional programs driven by the orphan nuclear receptor NR2F2.Results: We uncovered that astrocyte NF-kB activation and fear behavior were promoted by inflammatory monocyte recruitment to the brain meninges during chronic stress, which was reversed, alongside fear behavior, by psychedelic administration.Conclusion: These data, together with validation in clinical samples, suggest that psychedelics can be used to target neuroimmune interactions relevant to neuropsychiatric disorders and potentially other inflammatory diseases.