Chronic cannabinoid vapor exposure: Long-term effects on myelin, functional neural networks, and behavior - Abstract Inhalation is the most common route of administration of cannabis products, and vaping of delta-9- tetrahydrocannabinol (THC) results in more rapid delivery of drug to the brain, higher concentrations in brain and blood, greater subjective effects, and greater impairment compared to other routes of administration. The potential harms associated with chronic vaping of THC are largely unknown; however, chronic use of THC and cannabis has been linked with increased risks of anxiety and other mood disorders, psychosis, and cannabis use disorder. Retrospective studies in adults who regularly use cannabis use have observed structural and functional brain abnormalities, cognitive impairments and mood disorders, though the extent to which this is caused by THC is unknown. Given the rapidly increasing use of THC-containing cannabis vape products in the United States it is vital to increase our understanding of the impact of chronic vaporized THC on the brain. This multidisciplinary project aims to determine whether chronic vaporized delta-9-tetrahydrocannabinol (THC) exposure causes lasting behavioral and brain alterations, including disrupted connectivity, white matter damage, and neuroinflammation in adult male and female rats. Our central hypothesis is that repeated exposure to THC vapor increases neuroinflammation, which triggers inflammatory driven changes to white matter including degradation and damage, and results in persistent disruptions in neural connectivity and associated behavioral deficits. We will test this hypothesis by assessing the long-term effects of chronic THC vapor exposure on executive function, anxiety-like behavior, and functional connectivity (Aim 1); white matter integrity and myelin plasticity (Aim 2); and changes to the neuro-immune landscape by assessing inflammatory biomarkers, immune cell population signatures, and microglial and astrocytic molecular dynamics. Additionally, we will test whether reducing inflammation prevents THC-induced white matter damage and behavioral deficits (Aim 3). To achieve these objectives, we will use innovative cannabinoid vaporization technology and validated THC vapor dosing protocols along with translational behavioral assessments of executive function and anxiety- like behavior, preclinical functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), electron microscopy and immunohistochemistry for rigorous evaluation of myelin plasticity, validated bioassays of immune markers, glial morphology, as well as flow cytometry. This research will elucidate key mechanisms underlying long-term structural and functional brain changes caused by chronic THC vapor exposure, ultimately, informing public health guidelines on use of THC-containing vape products and guiding future lines of research into mechanisms of neurorepair.
