Behavioral and Molecular Effects of Antenatal SSRI Exposure

描述（由申请人提供）：此申请描述了一个为期四年的儿科学术生涯培训计划。首席研究员在密歇根儿童医院/韦恩州立大学医学院完成了儿科住院医师培训，并在波士顿儿童医院/哈佛医学院完成了儿科急诊医学和医学毒理学的奖学金培训。现在，他将通过凯斯西储大学（CWRU）神经科学系、环境健康科学系和儿科系（分别是首席研究员的一级和二级部门）之间独特的跨部门合作，扩展他的科学技能。跨部门合作将为首席研究员提供指导研究、职业发展和培训活动，使其成为一名独立研究者。该计划将促进控制脊椎动物5-羟色胺（5-HT）系统发育的调节程序，以及其在产前选择性5-羟色胺再摄取抑制剂（SSRI）暴露扰动后的状况。Evan Deneris博士将指导首席研究员的科学发展，他是脑5-羟色胺神经递质系统分子遗传学领域公认的领导者。他为理解在整个生命周期中调节5-羟色胺系统功能的遗传机制以及这些机制如何影响5-羟色胺调节行为做出了根本性贡献。他的研究已经确定了Pet-1转录因子在胚胎调控网络中起作用，以指定小鼠腹侧后脑中的5-HT神经元。Deneris博士是神经科学系的教授，培养了许多研究生和博士后。此外，一个由备受尊敬的CWRU研究人员组成的咨询委员会将提供科学和职业指导。通过鉴定Pet-1顺式调控区域，使BAC转基因工具成为可能，该区域指导发育和成年大脑5-HT神经元中转基因的高度可重复表达，Deneris博士开发了ePet-EYFP转基因小鼠系，其5-HT神经元在整个生命周期中都被增强的黄色荧光蛋白（EYFP）遗传标记。这些小鼠允许前所未有的5-HT神经元和靶向基因表达研究，特别是在生命的任何阶段的5HT神经元。拟议的实验将需要怀孕的ePet-EYFP小鼠产前暴露于SSRI氟西汀。随后，后代的表型将使用行为分析和分子技术进行检查。具体目的包括：1)建立ePet-EYFP小鼠作为产前SSRI暴露行为发病机制的有效模型；2)研究ePet-EYFP小鼠产前SSRI暴露的分子效应。在ePet-EYFP小鼠中结合行为和分子方法在基础心理健康研究中是独一无二的。他们将共同验证首席研究员的假设，即产前暴露于SSRI会导致控制5-HT神经元发育的调节程序的扰动导致行为发病机制。

DESCRIPTION (provided by applicant): This application describes a 4-year training program for an academic career in pediatrics. The Principal Investigator (Principal Investigator) has completed residency training in pediatrics at Children's Hospital of Michigan/Wayne State University School of Medicine and fellowship training in both pediatric emergency medicine and medical toxicology at Children's Hospital of Boston/Harvard Medical School. He will now expand upon his scientific skills through a unique inter-departmental collaboration between the Department of Neurosciences and the Departments of Environmental Health Sciences and Pediatrics, the Principal Investigator's primary and secondary departments, respectively, at Case Western Reserve University (CWRU). The inter-departmental collaboration will provide the Principal Investigator with mentored research, career development, and training activities for a future career as an independent investigator. This program will promote the command of the regulatory programs that govern the development of the vertebrate serotonin (5-HT) system, and its condition after perturbation with antenatal Selective Serotonin Reuptake Inhibitor (SSRI) exposure. Dr. Evan Deneris will mentor the Principal Investigator's scientific development and is a recognized leader in the field of molecular genetics of the brain 5-HT neurotransmitter system. He has made fundamental contributions to the understanding of the genetic mechanisms that act across the lifespan to regulate 5-HT system function and how these mechanisms impact 5-HT modulated behaviors. His studies have identified the Pet-1 transcription factor that functions in an embryonic regulatory network to specify 5-HT neurons in the mouse ventral hindbrain. Dr. Deneris is a Professor in the Department of Neurosciences and has trained numerous graduate students and postdoctoral fellows. Also, an Advisory Committee of highly-regarded CWRU investigators will provide scientific and career guidance. Using BAC transgenic tools that were made possible by the identification of the Pet-1 cis regulatory region that directs highly reproducible expression of transgenes in developing and adult brain 5-HT neurons, Dr. Deneris developed the ePet-EYFP transgenic mouse line whose 5-HT neurons are genetically marked with enhanced yellow fluorescent protein (EYFP) throughout the lifespan. These mice allow for unprecedented access to 5-HT neurons and targeted gene expression studies specifically in 5HT neurons at any stage of life. The proposed experiments will entail antenatal exposure of pregnant ePet-EYFP mice with the SSRI, fluoxetine. Subsequently, phenotypes of offspring will be examined using behavioral assays and molecular techniques. The specific aims include: 1) Establishing the ePet-EYFP mouse as a valid model of behavioral pathogenesis resulting from antenatal SSRI exposure, and 2) Investigating the molecular effects of antenatal SSRI exposure in ePet-EYFP mice. The combined behavioral and molecular approach in ePet-EYFP mice is unique in basic mental health research. Together, they will test the Principal Investigator's hypothesis that antenatal SSRI exposure will lead to behavioral pathogenesis from perturbations in the regulatory programs that govern 5-HT neuron development.