Neurogenesis and chronic cannabinoid exposure

描述（由申请人提供）：大麻素越来越多地用于慢性疾病的治疗，因此了解其长期影响非常重要。大麻素在发育和成人神经系统中调节神经发生，但实际上对其对青少年和衰老大脑的神经发生的影响一无所知。大麻素对神经发生的影响可能会在整个生命过程中有所不同，因为中枢神经系统仍在青春期发育，而神经发生的能力在衰老过程中会下降。该项目的目的是确定慢性暴露于大麻素如何影响神经发生，通过细胞增殖，分化和生存来衡量，在整个生命中。我们的中心假设是大麻素系统的慢性外源性调节将根据发育阶段不同改变神经发生。这项研究的基本原理是需要了解外源性大麻素对成人神经发生的长期影响，目前尚不清楚。如果没有这些信息，治疗慢性疾病（如关节炎疼痛）的适当疗法和成瘾干预就不能安全实施。我们将利用青少年，成年和老年小鼠来验证我们的中心假设，以确定大麻的主要精神活性成分- 9-四氢大麻酚（THC）和合成大麻素对两个神经发生区域，齿状回和嗅觉上皮的神经发生的慢性影响。目前，还没有治疗大麻素成瘾的药物；然而，目前正在开发CB1拮抗剂作为潜在的治疗药物。因此，我们也将评估CB1拮抗剂对神经发生的慢性影响。此外，大麻素可以调节出生后和成年动物的祖细胞是否向神经元或神经胶质细胞转移。与神经元相比，长期暴露于外源性大麻素可以显著改变祖细胞成熟为胶质细胞的比例，无论发育阶段如何。大脑区域细胞组成的改变会对功能产生不利影响。这个拟议的小型研究项目将提供大麻素在整个发育过程中对神经发生的慢性影响的详细了解。所获得的信息可能描述了积极的，神经保护作用，如在老年人中增加神经发生，以及有害的影响，如在青少年中改变神经发生。总的贡献将是重大的，因为它将为发展改进和安全的治疗策略提供基础。

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.