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，尽管在理解精神分裂症的病理生理学方面取得了重大进展， 在这种疾病的发展中，可用的治疗将不会在显著的患者亚组中产生响应。 这一事实，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 需要新的方法来理解精神分裂症的病理生理学和开发新的治疗方法。 肠道微生物组已成为人类神经精神疾病和行为障碍的贡献者。 在啮齿类动物中的变化，但尚未在精神分裂症的背景下进行广泛研究。有趣的是， 已证明微生物组会影响血清素5-HT 2A受体的表达，该受体已被证实 与人类精神分裂症以及该疾病的动物模型密切相关。我们集团 研究表明，来自人类精神分裂症患者的无抗精神病药尸检样本和 精神分裂症母体免疫激活模型中的后代小鼠显示出增加的 前额叶皮层的受体。该模型中的小鼠也显示出精神病样5-HT 2A的增加率。 受体依赖性头部抽搐反应。其他研究小组已经证明了受体与 精神分裂症相关表型，如皮质锥体神经元和感觉运动门控功能改变 赤字因此，我们建议研究肠道微生物组在5-HT 2A受体发育中的作用 流感病毒诱导的母体免疫中的改变和随后的精神分裂症样表型 小鼠精神分裂症激活模型。转基因小鼠，分子生物学技术，啮齿动物行为 分析和显微镜将用于实现这些目标。我们的研究结果有可能进一步 了解精神分裂症的病理生理学和肠道微生物组在精神分裂症中的意义 将允许研究新的治疗和预防目标。 培训计划建议通过介绍以下内容来发展申请人的科学和临床能力： 与分子生物学、小鼠行为、树突棘分析相关的实验技术， 操纵肠道微生物组;发展基本技能，如科学交流，统计 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 通过研讨会和期刊俱乐部等途径增加科学知识。的 拟议的研究将发生的环境拥有进行研究所需的设备。 工作、包括显微镜和转基因小鼠核心在内的丰富核心设施以及具有专业知识的教师 在广泛的领域，包括精神病遗传学，显微镜和神经科学。

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.