Grant: Doctoral Research Award: Canada Graduate Scholarships

Psychedelic drugs have become increasingly relevant to clinical settings as recent research has unveiled their powerful effects in alleviating mental health disorders. Specifically, psilocybin, the main active compound in 'magic mushrooms', has demonstrated surprising effectiveness in treating major depressive disorder (MDD)-characterized by degradation of key circuits in the frontal and temporal lobes of the brain. Psilocybin is known to act through the brain's serotonin system, particularly on serotonin receptor 2A, but the cellular and molecular consequences of psilocybin's actions in the brain-which lead to beneficial changes in key circuits and improved mental health-remain mysterious. Microglia are the immune cells of the brain which, on top of removing toxic waste products and responding to injury and infection, are responsible for altering and preserving the connections within brain circuits. The impact of psilocybin on microglia has not yet been investigated. We propose that the beneficial effects of psilocybin are driven by its ability to modify the actions of microglia which will lead to a regrowth of degraded brain circuitry. Therefore, using a mouse model of MDD, we will measure the influence of psilocybin on microglia using molecular analyses and microscopy and relate those to changes with MDD-like behaviours in mice. Additionally, through altering the genetic profile of the mice, we will remove (1) microglia from the brain and (2) microglia-specific serotonin receptor 2A selectively to isolate the cell- and receptor-specific influences of psilocybin treatment on the brain and behaviour. This research will shape the scientific understanding of the impact of psychedelic substances on brain circuitry and behavioural outcomes, as well as unravel new microglial targets for treating mental health disorders, particularly MDD. Most importantly, this research will aid in the development of new treatments for Canadians suffering from mental health disorders.