Psilocybin effects on brainwide activity dynamics supporting accelerated task acquisition - PROJECT SUMMARY / ABSTRACT This proposal aims to investigate the systems-level brain mechanisms underlying the therapeutic potential of psilocybin, a psychoactive compound that has attracted recent attention for the treatment of anxiety, depression, addiction, pain, and illness-associated distress. Despite promising outcomes in clinical trials, the specific mechanisms governing psilocybin's medicinal effects remain poorly understood. Our preliminary data reveal a novel dissociation between two major effects of a single dose of psilocybin: serotonergic receptor activation mediates acute behavioral changes, while BDNF/TrkB signaling drives improvements in learning and motivated behavior lasting for weeks after a single dose of drug administration. We will explore these psilocybin-driven changes in behavioral states and motivated task acquisition and identify the cellular and brainwide substrates, from dendritic spines to large-scale brain networks. Aim 1 examines the accelerated acquisition of motivated behavior components within an evidence accumulation task. In preliminary results, psilocybin specifically enhances stages requiring changes in action control rather than working memory capacity. Pharmacological studies so far show that ketanserin blocks acute effects but preserves learning enhancement, while TrkB antagonist ANA-12 blocks learning enhancement but not acute effects. Using transgenic mice lacking the TrkB allosteric site, we will next test whether psilocybin's learning effects require action upon the neurotrophin pathway. Trial-by-trial and within-trial analyses will quantify attentional state, sensory integration, and learning rate. In freely moving mice, we will perform automated pose tracking to quantify social behavior and motivation. Aim 2 identifies cellular and brainwide substrates of psilocybin-induced functional change. Our preliminary data from mouse brain sections show that training combined with psilocybin leads to reduced dendritic spine density specifically in task-relevant cortical regions, suggesting enhanced circuit refinement. Using AI-based spine detection and in vivo multiphoton imaging, we will track spine dynamics over extended periods. These methods will be applied to wild-type and TrkB-allosteric-knockout mice to evaluate whether dendritic spine plasticity is co-regulated with learning acceleration. Using automated analysis of activity- dependent neuronal c-Fos expression with light-sheet microscopy, we will further perform a brainwide association study to identify regions and co-activated networks supporting enhanced task acquisition. The breakthrough therapy status granted to psilocybin underscores its therapeutic potential. This proposal seeks to advance our understanding of psilocybin's brain circuit-level mechanisms, with the goal of developing interventions that preserve therapeutic benefits while minimizing unwanted effects. The results will guide future neurophysiological investigations and more effective psilocybin-based treatments for mental health concerns.
