Exploring the neural architecture of psychedelic experience with high-density electrophysiology

About This Grant

PROJECT ABSTRACT Major Depressive Disorder affects millions of Americans, many of whom do not respond to traditional antidepressants. Psychedelics, like psilocybin, offer a promising new therapeutic avenue, producing rapid and sustained benefits after a single dose. Research on the psychedelic psilocybin has revealed altered neuronal activity across many brain regions post-psilocybin exposure, but these studies often rely on low-resolution imaging like fMRI and therefore unable to resolve the single-neuron dynamics that drive these changes. Consequently, psilocybin’s precise impact on neural spiking, network communication, their temporal evolution, and neural correlates of behavioral alterations remains largely unexplored. This project will address this gap by using cutting-edge Neuropixels probes for chronic, high-density electrophysiology during freely moving behavior in male and female mice. This approach will allow for an unprecedented view of single-neuron activity across multiple brain regions over weeks. The project’s specific aims are: (1) To identify psilocybin's longitudinal impact on brain-wide neural dynamics during cognitive and social behaviors. (2) To elucidate the neural changes underlying psilocybin-induced resilience to stress using a chronic variable stress model of depression. This F31 fellowship training plan is designed to provide the applicant with essential skills in advanced surgery, behavioral neuroscience, and data analysis. The training will be conducted at Johns Hopkins University, a premier environment for both neuroscience and psychedelics research, under the guidance of a world-class multi-disciplinary mentorship team. The proposed research will create a foundational, high-resolution dataset of psilocybin’s neural effects, and elucidate the location, timing, and nature of altered neural activity across the brain following a single dose. Activities under this fellowship will equip the applicant with the skillset necessary for a career as an independent investigator focused on neuropsychiatric disorders.