Adolescent cannabinoid exposure in a rodent model of schizophrenia susceptibility

 描述(申请人提供)：该项目旨在探索遗传和环境因素在精神病症状发展过程中的相互作用。青春期接触大麻与患精神分裂症的风险增加有关，但这种相关性并不是因果关系。因此，具有精神病症状遗传易感性的人很可能更容易受到环境风险因素的影响。我们已经建立了一种动物模型，通过使用第二代子代(F2)的大鼠，这些大鼠被甲基氮氧基甲醇醋酸酯(MAM)破坏发育，增加了对精神分裂症样症状的易感性。我们假设青春期的大麻素暴露会增加这些“F2 MAM”大鼠表现出精神分裂症样表型的比例。这种表型将在行为水平(刺激剂诱导的多动、社会互动和注意力定势转移)、细胞水平(自发)进行评估 多巴胺神经元活性和海马锥体活性)，以及分子水平(抑制性标志物的表达)。了解风险因素的相加或交互影响可以让我们对出现精神病症状做出更准确的预测，并为那些已经处于风险中的人提供个性化的警告。此外，敏感性模型对预防性实验疗法非常有用。这项建议将为未来的独立研究人员提供重要的实验设计、实验室和分析技术、伦理和其他基本技能方面的培训。

 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.