PROJECT SUMMARY Psychedelics are increasingly studied as a potential treatment for mental illnesses. For example, recent clinical trials showed positive outcomes after psilocybin-assisted psychotherapy for patients with major depressive disorder. The results are notable because of the durability of the beneficial effects after one or two dosing sessions, in which significant reduction of symptoms was detectable for at least several weeks and potentially up to several months. Although the neurobiology responsible for the potential therapeutic effect remains unclear, it has been suggested that neural plasticity in cortical pyramidal cells may be a contributing factor. However, pyramidal cells are embedded in cortical microcircuits and interact closely with GABAergic interneurons. The extent to which major interneuron subtypes may contribute to the psilocybin-induced changes in neural plasticity and behavior is unknown. The goal of this proposal is to determine the effects of psilocybin on the three major subtypes of GABAergic interneurons in the mouse medial frontal cortex. In Aim 1, we will use cell type-specific electrophysiology to measure how each cell type respond in spiking activity to the administration of psilocybin. In Aim 2, we will determine whether serotonin receptors that are expressed in the interneurons may be mediating psilocybin’s plasticity-promoting actions. In Aim 3 we will test if manipulating interneuron activity may alter psilocybin’s effect on stress-related behaviors. These experiments are designed to provide insights into how the excitatory-inhibitory microcircuit may shape the action of psilocybin in the neocortex and to identify cell types that are essential for the effects of psilocybin on neural plasticity and behavior.

PROJECT NARRATIVE Classical psychedelics such as psilocybin are being investigated as potential treatment for major depression. It is known that psilocybin can induce neural plasticity in the neocortex, however the brain region contains many different cell types and how they may interact to mediate drug action is not known. This proposal seeks to address this knowledge gap, which can provide insights into the neurobiology of psilocybin and may lead to better treatments for depression.