Neurogenesis and chronic cannabinoid exposure

描述(申请人提供)：大麻类物质越来越多地被用于治疗慢性病，因此了解其长期影响极其重要。大麻素在发育过程中和成人神经系统中调节神经发生，但几乎不知道它们对青少年和老化大脑中神经发生的影响。由于中枢神经系统在青春期仍在发育，而神经发生的能力在衰老过程中下降，因此大麻类化合物在一生中可能对神经发生有不同的影响。该项目的目标是确定长期暴露于大麻类物质如何影响神经发生，通过细胞增殖、分化和存活来衡量，在整个生命过程中。我们的中心假设是，根据发育阶段的不同，对大麻素系统的慢性外源性调节将不同地改变神经发生。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，就不能安全地实施适当的治疗方法来治疗慢性疾病，如关节炎疼痛和成瘾干预。我们将利用青少年、成年和老年小鼠来测试我们的中心假设，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源性区域--齿状回和嗅觉上皮--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，CB1拮抗剂目前正在被开发为潜在的治疗剂。因此，我们还将评估CB1拮抗剂对神经发生的慢性影响。此外，在出生后和成年动物中，大麻素调节祖细胞是否致力于神经元或神经胶质细胞。与神经元相比，长期暴露于外源性大麻素可以显著改变成熟为神经胶质的前体细胞的比例，无论发育阶段如何。大脑区域细胞组成的变化可能会对功能产生不利影响。这个拟议的小型研究项目将详细了解大麻类物质在整个发育过程中对神经发生的慢性影响。所获得的信息可能描绘出积极的神经保护作用，如老年人神经发生的增加，以及有害的影响，如青少年的神经发生改变。总体贡献将是巨大的，因为它将为改进和安全的治疗战略的发展提供基础。

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.