Gut dysbiosis and 5-HT2A dysregulation in a preclinical schizophrenia model

项目摘要/摘要 精神分裂症的病理生理学是复杂的，尽管在理解 在这种疾病的发展过程中，现有的治疗方法不会在很大一部分患者中产生反应。 这一事实，再加上与目前可用的抗精神病药物相关的显著发病率，突出了 需要新的方法来了解精神分裂症的病理生理学和开发新的治疗方法。 肠道微生物群已经成为人类神经精神障碍和行为障碍的贡献者 在啮齿动物中的变化，但还没有在精神分裂症的背景下进行广泛的调查。有趣的是， 微生物组已被证明影响5-HT2A受体的表达，该受体已被 在人类精神分裂症和这种疾病的动物模型中都有很好的牵连。我们的团队已经 无论是精神分裂症患者的非抗精神病药物尸检样本，还是 精神分裂症母体免疫激活模型中的子代小鼠显示出密度增加的 前额叶皮质中的受体。该模型中的小鼠也表现出类似精神病的5-HT2a的增加。 依赖受体的头部抽动反应。其他研究小组已经证明了该受体与 精神分裂症相关表型，如皮质锥体神经元功能改变和感觉运动门控 赤字。因此，我们建议研究肠道微生物组在5-HT2A受体发育中的作用。 流感病毒诱导的母体免疫中的变化和随后的精神分裂症样表型 精神分裂症小鼠的激活模型。转基因小鼠，分子生物学技术，啮齿动物行为 化验和显微镜将被用来实现这些目标。我们的结果有可能进一步 对精神分裂症病理生理的认识及肠道微生物群在精神分裂症中的意义 将允许对治疗和预防的新目标进行调查。 培训计划建议通过介绍以下内容来培养申请者的科学和临床能力 与分子生物学、老鼠行为、树突棘分析相关的实验技术 肠道微生物群的操作；基本技能的发展，如科学交流、统计学 分析、假设生成和检验以及伦理学；在医学院期间加强临床技能 书记员；以及通过研讨会和期刊俱乐部等场所增加科学知识。这个 拟进行研究的环境具备进行研究所需的设备 工作，丰富的核心设施，包括显微镜和转基因小鼠核心，以及具有专业知识的教师 在包括精神遗传学、显微镜和神经科学在内的广泛领域。

Project Summary/Abstract The pathophysiology of schizophrenia is complex and, despite significant advances in understanding the development of this disorder, available treatments will not produce a response in a significant subset of patients. This fact, combined with the significant morbidity associated with currently available antipsychotics, highlights a need for novel approaches to understanding schizophrenia pathophysiology and developing new treatments. The gut microbiome has emerged as a contributor to neuropsychiatric disorders in humans and behavioral alterations in rodents, but has not been extensively investigated within the context of schizophrenia. Interestingly, the microbiome has been demonstrated to affect expression of the serotonin 5-HT2A receptor, which has been well implicated within human schizophrenia as well as animal models of the disorder. Our group has demonstrated that both antipsychotic-free postmortem samples from human schizophrenia patients and offspring mice within a maternal immune activation model of schizophrenia display increased density of the receptor in the prefrontal cortex. Mice within this model also display increased rates of the psychosis-like, 5-HT2A receptor-dependent head twitch response. Other groups have demonstrated association of the receptor with schizophrenia-related phenotypes such as altered function of cortical pyramidal neurons and sensorimotor gating deficits. We therefore propose to investigate the role of the gut microbiome in the development of 5-HT2A receptor alterations and subsequent schizophrenia-like phenotypes in an influenza virus-induced maternal immune activation model of schizophrenia in mice. Transgenic mice, molecular biology techniques, rodent behavioral assays, and microscopy will be used to accomplish these goals. Our results have the potential to further understanding of the pathophysiology of schizophrenia and implication of the gut microbiome in schizophrenia would allow for investigation into new targets for therapy and prevention. The training plan proposes to develop the applicant’s scientific and clinical abilities via introduction to experimental techniques relevant to molecular biology, mouse behavior, dendritic spine analysis, and manipulation of the gut microbiome; development of essential skills such as scientific communication, statistical analysis, hypothesis generation and testing, and ethics; enhancement of clinical skills during medical school clerkships; and addition of scientific knowledge through venues such as seminars and journal clubs. The environment in which the proposed research will take place possesses the equipment necessary to conduct the work, a wealth of core facilities including the Microscopy and Transgenic Mouse cores, and faculty with expertise in a breadth of areas including psychiatric genetics, microscopy, and neuroscience.