PROJECT SUMMARY Psychedelics are chemicals best known for their ability to induce profound changes in the human conscious experience. After a several-decade hiatus, research on psychedelics is undergoing a renaissance, driven by their potential to treat psychiatric disorders with rapid onset and enduring effect. Recent research reveals that psychedelics can rapidly promote the structural and functional plasticity of synapses, leading to the conjecture that neural plasticity underlies their long-term therapeutic values. However, the neurobiological mechanisms remain largely elusive. Our overarching goal is to understand the cellular and circuit mechanisms underlying psychedelics’ long-lasting therapeutic effects. In this proposal, we focus on the classical serotonergic psychedelic psilocybin and investigate how it rescues the deleterious effects of stress, a major risk factor for many neuropsychiatric disorders. Our central hypothesis is that psilocybin affects the brain at multiple levels, from synaptic plasticity to the functional network; although psilocybin only transiently enhances synapse formation, it permanently alters the synaptic circuit in an experience-dependent manner; the incorporation of new synapses into the neural circuit is essential for psilocybin’s long-lasting rescue of stress-induced functional and behavioral deficits. Specifically, in Aim 1, we will determine the acute and enduring effects of psilocybin on the stressed brain, particularly on the structural reorganization of synaptic circuits, on cortical functional networks, and on the representation of behavioral variables by cortical neuronal ensembles. Aim 2 determines how the environmental and behavioral contexts in which psilocybin is administered impact its rescuing effects on the stressed brain. Aim 3 determines the contribution of psilocybin-induced neuroplasticity, particularly the stabilization of newly formed dendritic spines, to its rescuing effects on the stressed brain. Overall, these studies will provide an integrated, mechanistic understanding of psilocybin’s rescuing effects across the organizational hierarchy of the brain, from molecules and synapses to circuits and functional networks, and lay the foundation for its clinical application in treating stress-related psychiatric disorders.

PROJECT NARRATIVE This proposal studies how the classical psychedelic psilocybin rescues the deleterious effects of chronic stress, a major risk factor for mental illnesses. We investigate psilocybin’s effects across the brain’s organizational hierarchy, from synapses and neural circuits to large-scale cortical networks and ultimately mouse behavior. Such studies will reveal the fundamental mechanisms of psychedelics’ impact on brain and behavior and provide an integrated, mechanistic foundation for their applications in psychiatry.