Persistent Impacts of Adolescent THC on Microglial Function and Opioid Addiction Risk

Project Summary Adolescent cannabis use has been linked to negative long-term outcomes in humans, including increased rates of experimentation with “harder” drugs like opioids later in life. Yet these associations cannot be tested causally in humans, so animal studies showing that adolescent THC exposure (adoTHC) indeed causes developmental disruption of reward and cognition circuits are notable and potentially alarming. Here we employ a well- characterized, translationally-oriented adoTHC exposure model in rats to examine how opioid-addiction relevant behaviors are altered, and to uncover novel brain mechanisms by which these behavioral changes may manifest. Notably, microglia, the resident immune cells of the brain, are increasingly being recognized for their key roles in neurodevelopment, including in adolescence. In pursuit of a mechanistic understanding that can inform novel interventions or strategies for opioid addiction, my project examines the effects of adoTHC exposure on microglia, and how these changes may impact opioid drug seeking behavior. I employ translationally relevant behavioral models of opioid addiction in rats to fully characterize the adoTHC- induced pro-opioid phenotype, and employ both hypothesis-generating RNA sequencing approach, as well as an experimental microglial “resetting” approach to test the causal relevance of microglia in the observed pro- opioid behavioral phenomena seen in males and females. During the F99 phase of this award, I will replicate and extend my findings, and obtain training and new data employing RNA sequencing of FACS-isolated microglia in prefrontal cortex. The proposed training will facilitate my transition to a competitive postdoctoral position focused on in vivo imaging and monitoring of microglia, building upon my current expertise in addiction behavioral models. My sponsors will be instrumental in helping me build skills in experimental design, guided analyses support, scientific communication, and grantsmanship. They will also guide me in finding a postdoctoral training environment focused in neuroimmunology aligning with my long-term research and career goals. Altogether, the F99/K00 award serves as an invaluable asset in propelling me on a trajectory towards becoming a tenure-track addiction behavioral neuroscientist.