PROJECT TITLE Subcortical targets involved in the action of psilocybin in learned and innate escape behaviors PROJECT SUMMARY Mood disorders such as depression now represent a leading cause of disability throughout the world, with conventional first-line treatments failing to provide relief for most patients. In recent years, novel treatments with fast-acting properties have garnered significant interest as innovative therapies. The psychedelic psilocybin, in particular has recently gained attention for its ability to produce substantial and rapid antidepressant effects in early-phase clinical trials. This combination of increasing need and exciting preliminary clinical results has led to the recent ‘breakthrough therapy’ status designation for psilocybin to be studied as a treatment for major depressive disorder. Yet despite these exciting results in pilot clinical trials, the neurobiology underlying the effect of psilocybin remains less understood. Thus, a critical opportunity to further our understanding of the action of psilocybin will be addressed here. Among early studies examining the mechanisms of action of psilocybin, most have focused on the neocortex and hippocampus. However, previous cellular and circuit-level research has clearly implicated subcortical structures as key in the action of psilocybin. Our own preliminary work using whole-brain cFos mapping has identified several candidate subcortical regions that are modulated by psilocybin. Aim 1 will determine the activity of two of these key subcortical brain regions via in vivo recording with high-density silicon probes to determine how neural activity changes following systemic psilocybin administration. Aim 2 will use causal manipulation during psilocybin treatment to determine the relative role of subcortical regions during innate and learned escape behaviors in mice. Specifically, chemogenetics will be used to bidirectionally control brain region activity during a looming stimulus and learned escape behavioral paradigms. Cumulatively, this work will determine the relative roles of key subcortical brain regions in the action of psilocybin during escape behaviors and expand the framework for psilocybin’s use in clinical treatment.