Neurogenesis and chronic cannabinoid exposure

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Cannabinoids are increasingly being used in the treatment of chronic diseases, making it extremely important to understand their long-term effects. Cannabinoids modulate neurogenesis during development and in the adult nervous system, yet virtually nothing is known about their effects on neurogenesis in the adolescent and the aging brain. There might be differential effects of cannabinoids on neurogenesis throughout life as the central nervous system is still developing in adolescence and the capacity for neurogenesis decreases during the aging process. The objective for this project is to determine how chronic exposure to cannabinoids effects neurogenesis, measured by cell proliferation, differentiation and survival, throughout life. Our central hypothesis is that chronic exogenous modulation of the cannabinoid system will differentially alter neurogenesis depending on the developmental stage. The rationale for this research is the need to understand the long-term effects of exogenous cannabinoids on adult neurogenesis, which are currently unknown. Without this information, appropriate therapeutics for treatment of chronic diseases, such as arthritic pain, and addiction intervention can not be safely implemented. We will test our central hypothesis utilizing adolescent, adult and aged mice to ascertain the chronic effects of ¿9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana, and synthetic cannabinoids on neurogenesis in two neurogenic regions, the dentate gyrus and the olfactory epithelium. Currently, there are no medications available to treat cannabinoid addiction; however, CB1 antagonists are currently being developed as potential therapeutic agents. Therefore, we will also assess the chronic effects of CB1 antagonists on neurogenesis. In addition, cannabinoids modulate whether progenitor cells commit to neurons or glia in both post-natal and adult animals. Chronic exposure to exogenous cannabinoids could significantly alter the proportion of progenitor cells that mature into glia as compared to neurons, regardless of the developmental stage. Change in the cellular composition of a brain region could adversely affect function. This proposed small research project will provide a detailed understanding of the chronic effects of cannabinoids on neurogenesis throughout development. Information gained may delineate both positive, neuroprotective effects, as in increased neurogenesis in the aged, as well as detrimental effects, as in altered neurogenesis in the adolescent. The overall contribution will be significant in that it will provide the basis for the development of improved and safe therapeutic strategies.