Neurogenesis and chronic cannabinoid exposure

神经发生和慢性大麻素暴露

• 批准号: 8445629
• 负责人: COLLEEN Cosgrove HEGG
• 金额: $ 7.68万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445629
• 关键词: Adolescence; Adolescent; Adult; Adverse effects; Affect; Aging; Aging-Related Process; Agonist; Apoptotic; Arthritis; Brain; Brain region; CNR1 gene; CNR2 gene; Cannabinoids; Cannabis; Cell Proliferation; Cessation of life; Chronic; Chronic Disease; Commit; Data; Development; Elderly; Embryo; Endocannabinoids; Exposure to; Intervention; Lead; Life; Ligands; Long-Term Effects; Marijuana; Marijuana Abuse; Measures; Mediating; Mus; Nervous system structure; Neuraxis; Neuroglia; Neurons; Olfactory Epithelium; Outcome; Pain; Pharmaceutical Preparations; Pharmacy (field); Plants; Process; Production; Public Health; Receptor Activation; Research; Research Project Grants; Staging; Stem cells; System; Testing; Tetrahydrocannabinol; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic Uses; Time Study; addiction; adult neurogenesis; age group; aged; aging brain; analog; base; cannabinoid receptor; chronic pain; dentate gyrus; improved; indexing; mature animal; neurogenesis; prophylactic; public health relevance; receptor

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.

描述（由申请人提供）：大麻素越来越多地用于治疗慢性疾病，这使得了解大麻素在发育过程中和成人神经系统中调节神经发生的长期作用变得极其重要，但实际上对其一无所知。对青少年和衰老大脑的神经发生的影响 大麻素对整个一生的神经发生可能有不同的影响，因为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。该项目的目标是确定长期接触大麻素如何影响神经发生，通过细胞增殖、分化和存活来衡量，我们的中心假设是大麻素系统的长期外源性调节将根据发育阶段的不同而不同地改变神经发生。这项研究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，就无法安全地使用适当的疗法来治疗关节炎疼痛等慢性疾病和成瘾干预。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 ¿ 9-四氢大麻酚 (THC) 是大麻的主要精神活性成分，而合成大麻素对两个神经源区域（齿状回和嗅觉上皮）的神经发生有影响，但目前尚无药物可用于治疗大麻素成瘾；因此，我们还将评估 CB1 拮抗剂对神经发生的慢性影响。与神经元相比，长期接触外源性大麻素可能会显着改变出生后和成年动物的神经元或神经胶质细胞，无论大脑区域的细胞组成如何变化。这个拟议的小型研究项目将详细了解大麻素对整个发育过程中神经发生的慢性影响，所获得的信息可能会描述积极的神经保护作用，例如增加老年人的神经发生，以及不健康的影响。总体贡献将是显着的，因为它将为开发改进和安全的治疗策略提供基础。