Characterizing the novel activity of THC directly at the androgen receptor on masculinization of the brain

About This Grant

Project Summary The brain's development is a complex interplay among the nervous, endocrine, and immune systems. Disruption of any of these systems can disturb the delicate balance of normal neurodevelopment, increasing the risk of neuropsychiatric diseases later in life. The developing brain is characterized by its sensitivity to gonadal steroid hormones, particularly androgens produced by the fetal testis during the perinatal period. The surge of androgens from the fetal testis establishes the critical period of masculinization, during which androgen-sensitive brain regions undergo morphological and functional changes to prepare males for appropriate behaviors later in life, such as mating and aggression. The ability of androgens to organize neural substrates depends on the direct or indirect activity of the androgen receptor. The androgen receptor is a nuclear steroid receptor capable of binding to the promoter regions of specific genes, many of which function as epigenetic modifiers to alter transcriptional regulation. In addition to these direct effects, the androgen receptor has been shown to recruit the immune system through cannabinoid signaling to promote the masculinization of androgen-sensitive brain regions. The relationship between androgens and endocannabinoids creates a delicate balance during neurodevelopment, as endocannabinoids are potent regulators of neuroimmune molecules involved in homeostasis and pathology. With recent changes in legalization and shifts in cultural perspectives on cannabis, there has been an increase in cannabis consumption during pregnancy, which has been associated with a heightened risk of neuropsychiatric disease in offspring, possibly due to the disruption of the delicate endocannabinoid system recruited by androgens. However, our recent work highlights an additional and direct role of cannabis, primarily its psychoactive component 9-tetrahydrocannabinol (THC), in disrupting androgen-mediated brain development. We demonstrate in silico that THC can bind to the androgen receptor with an affinity similar to that of testosterone, thereby creating the potential to directly affect brain development through actions at the androgen receptor. This proposal seeks to characterize this novel and unexplored action of THC through advanced structural and genomic techniques. In Aim I, I will characterize the binding kinetics of THC at the androgen receptor through surface plasmon resonance and identify ligand-induced conformational changes to the ligand binding domain of the androgen receptor through NMR spectroscopy. In Aim II, I will differentiate the effects of THC and testosterone on androgen receptors in regulating transcription within androgen-sensitive brain regions through ATAC-seq. These findings will highlight a previously uncharacterized role of THC and provide greater insights into the mechanisms through which gestational cannabis exposure alters normal androgen- mediated neurodevelopment and how it may contribute to the susceptibility of offspring to neuropsychiatric diseases later in life. Scientific mentorship from Drs. McCarthy, Weber, and Ament will provide me with unparalleled training to support a future career as a clinician-scientist in the field of child neurology.