Adolescent cannabinoid exposure in a rodent model of schizophrenia susceptibility

 描述（由申请人提供）：本项目旨在探索精神病症状发展中遗传和环境因素的相互作用。青少年时期接触大麻与患精神分裂症的风险增加有关，但这种相关性不是因果关系。因此，有精神病症状遗传倾向的人可能更受环境风险因素的影响。我们已经开发了一种动物模型，增加了精神分裂症样症状的易感性，通过使用第二代子代（F2）的大鼠，与甲基偶氮甲醇乙酸酯（MAM）发育中断。我们假设青春期大麻素暴露会增加这些“F2 MAM”大鼠显示精神分裂症样表型的比例。该表型将在行为水平（兴奋剂诱导的过度运动、社交互动和注意力转移）、细胞水平（自发）进行评估 多巴胺神经元活动和海马锥体活动）和分子水平（抑制性标记物的表达）。了解风险因素的叠加或交互作用可以使我们对精神病症状的发展做出更准确的预测，并为那些已经处于风险中的人提供个性化的警告。此外，易感性模型对于预防性实验治疗非常有用。该提案将为未来的独立研究者提供实验设计、实验室和分析技术、道德和其他基本技能方面的重要培训。

 DESCRIPTION (provided by applicant): This project aims to explore the interaction of genetic and environmental factors in the development of psychotic symptoms. Cannabinoid exposure during adolescence is associated with an increased risk of developing schizophrenia, but this correlation is not causative. Thus, it is likely that people with a genetic predisposition to psychotic symptoms are more strongly affected by environmental risk factors. We have developed an animal model with increased susceptibility to schizophrenia-like symptoms by using the second filial (F2) generation of rats that were developmentally disrupted with methylazoxymethanol acetate (MAM). We hypothesize cannabinoid exposure during adolescence will increase the proportion of these "F2 MAM" rats displaying a schizophrenia-like phenotype. This phenotype will be evaluated at the behavioral level (with stimulant-induced hyperlocomotion, social interaction, and attentional set-shifting), the cellular level (spontaneous dopamine neuron activity and hippocampal pyramidal activity), and the molecular level (expression of inhibitory markers). Understanding additive or interactive effects of risk factors could allow us to make more accurate predictions of developing psychotic symptoms, as well as personalize warnings for those already at risk. Furthermore, a model of susceptibility would be extremely useful for preventative experimental therapies. This proposal will provide important training in experimental design, laboratory and analytical techniques, ethics, and other essential skills for a future independent investigator.