PROJECT SUMMARY Psychiatric disorders are the leading cause of disabilities worldwide, and cost over $300B in the U.S alone. Despite the rise in psychiatric medication prescriptions, approximately 30% of patients are treatment resistant. Clinical trials indicate that psilocybin elicits rapid and sustained outcomes for mood and substance use disorders, sparking interest in the therapeutic potential of psychedelics. These effects are believed to be dependent on the serotonin-2A receptor subtype. However, serotonin exerts potent vasoactive effects, which becomes particularly relevant when employing functional magnetic resonance imaging (fMRI) to study the influence of psychedelics on neurophysiology. fMRI indirectly indexes neuronal activity via blood-oxygen-dependent signals which depend on neurovascular coupling (NVC). If NVC is altered, hemodynamic measures of brain activity may inaccurately reflect neuronal activity. Accurate assessment of the neurophysiological effects of psychedelics requires simultaneous mapping of neuronal and hemodynamic activity. That psychedelics alter brain structure and function is supported by molecular evidence demonstrating altered synaptic plasticity. Further, psychedelics can reactivate social critical periods in adult mice in a manner that aligns with the length of human-reported acute subjective effects (intoxication). These observations imply that psychedelics having longer versus shorter intoxication duration may differentially affect neuroplasticity. However, the potential for psychedelics to reopen critical periods beyond social reward circuitry is unknown, as is the impact of psychedelic duration on these processes. The central hypothesis of this proposal is that psychedelics give rise to differential reports of neuronal versus hemodynamic measures of neurophysiology and sensitize neuroplasticity in an intoxication-duration- dependent manner. I have been testing this hypothesis during my PhD research using wide-field optical imaging in awake mice under the influence of the psychedelic 2,5-Dimethoxy-4-iodoamphetamine (DOI). My preliminary results (Aim 1a) reveal that DOI significantly alters NVC, and that calcium (neuronal) and hemodynamic signaling differentially report how DOI alters brain network organization. For the remainder of my PhD, I will determine whether short- versus long-duration psychedelics differentially affect neurophysiology (Aims 1b, F99 Phase). For my postdoctoral research, I will determine whether psilocybin and DMT affect neuroplasticity in the visual system (Aim 2, K00 Phase). Specifically, I will test the hypothesis that psychedelics accelerate functional brain reorganization induced by monocular deprivation in a psychedelic intoxication-duration manner. Results from the proposed experiments will establish network-level neuronal signatures of psychedelics and determine whether psychedelics broadly enhance neuroplasticity. To guide my training, I have assembled an interdisciplinary team of mentors and collaborators at Washington University in St. Louis with diverse, complementary expertise. The outlined research and training plan will allow me to achieve my career goal of becoming an independent investigator designing novel treatment strategies for patients resistant to existing psychiatric therapies.

PROJECT NARRATIVE Chronic psychiatric disorders are the leading cause of disabilities worldwide, imposing substantial economic and societal burdens. Despite rises in psychiatric medications, >30% patients are treatment resistant, underscoring an urgency for innovative therapeutics. In this grant, we will systematically examine the acute and chronic effects of different psychedelics on murine neurophysiology.