Facilitating inhibition of fear with psilocybin: Mitochondria Dynamics and Mechanisms of Enhanced Plasticity

About This Grant

Background and Innovation: The psychedelic serotonin 5-HT2A agonist psilocybin has shown unprecedented efficacy in the treatment of depression and post-traumatic stress disorder (PTSD). Veterans are up to four times more likely to experience PTSD compared to non-Veterans. Vivid intrusive memories of traumatic events are a primary symptom of PTSD. An appreciation for the critical role of mitochondrial dynamics in learning and memory is emerging. Individuals with PTSD and depression exhibit signs of mitochondrial dysfunction, possibly contributing to the chronic nature of these psychiatric conditions. Intriguingly, agonism of the serotonin 5-HT2A receptor induces robust biogenesis of mitochondria. We hypothesize that increased mitochondrial biogenesis is a critical mediator of the therapeutic effects of psilocybin. In this VA Merit Award proposal, our studies model the intrusive memories of PTSD using Pavlovian fear conditioning in mice. The overarching hypothesis is that psilocybin rapidly induces mitochondrial biogenesis and enhances plasticity, making therapy (i.e., extinction of fear) more durable. Our goal is to determine whether compounds that modulate mitochondrial dynamics can improve the efficacy and efficiency of psilocybin. We will use novel transgenic mouse models to visualize mitochondrial dynamics in excitatory and inhibitory neurons in response to psilocybin alone and with nicotinamide mononucleotide (NMN). NMN is a safe precursor for nicotinamide adenine dinucleotide (NAD+), a coenzyme critical for many metabolic and signaling reactions. [Adequate NAD+ levels might prime the brain for psychedelic assisted therapy, enabling optimal brain energetics during extinction. We will determine whether enhanced mitochondrial dynamics are necessary for psilocbyin’s effects using genetic manipulations of NAD+dependent pathways in specific neuronal subtypes. Quantitative histology, behavioral outcomes, and ex vivo electrophysiology will determine whether administration of NMN can promote the effectiveness of psilocybin and enhance extinction of fear.] Significance and Impact to Veterans’ Health: PTSD is the most common mental health issue among Veterans served by the VA. Prolonged exposure therapy accounts for half of the treatment hours for Veterans in VA outpatient treatment clinics and dropout rates are high. Salient, traumatic memories permit neutral events, like a smell or place, to become associated with the trauma, thereby triggering traumatic memories. Individuals with PTSD fail to use contextual cues to modulate retrieval of fear memories regardless of whether the context is threatening or safe. These results suggest that the ability to control retrieval and suppress traumatic memories is disrupted. Dysregulated mitochondrial dynamics have been identified in individuals with PTSD. Mitochondrial dysfunction is an overlooked aspect of mood disorders that might pose an obstacle to therapeutic intervention, making reappraisal of traumatic memories inefficient. Using the translationally relevant fear-potentiated startle preparation, the proposed experiments will determine the effects of psilocybin with and without NMN and determine whether mitochondria-focused combination therapies enhance psychedelic assisted therapy. Pathway to Translation and Implementation: This proposal is focused on the development of safe adjuvants to facilitate psychedelic-assisted psychotherapies.[ Mitochondrial adaptation to experience is necessary for new learning to occur.] Supplements that modulate mitochondrial health and activity are currently used by millions of people to enhance longevity and metabolic efficiency. We will determine whether this class of supplements can prepare the brain to inhibit fear across contexts. We predict that these compounds can improve psilocybin assisted therapy, and potentially reduce the dose of psilocybin needed to facilitate exposure therapy. Current treatment protocols require a hallucinogenic dose that lasts 8 hours or more, making treatment less accessible, requiring long supervised therapy sessions. If successful, our results will make psychedelic assisted therapies more available to and successful for Veterans.