Behavioral and Molecular Effects of Antenatal SSRI Exposure

描述(由申请人提供)：本申请描述了一项为期4年的儿科学术生涯培训计划。首席调查员(首席调查员)已在密歇根儿童医院/韦恩州立大学医学院完成儿科住院医师培训，并在波士顿/哈佛医学院儿童医院完成儿科急诊医学和医学毒理学方面的研究员培训。他现在将通过神经科学系与环境卫生科学系和儿科系之间独特的跨部门合作来扩展他的科学技能。环境卫生科学系和儿科系分别是凯斯西储大学(CWRU)首席研究员的第一和第二系。部门间的合作将为首席调查员提供指导研究、职业发展和培训活动，为未来作为独立调查员的职业生涯做准备。该计划将促进对管理脊椎动物5-羟色胺(5-HT)系统的发展及其在产前暴露选择性5-羟色胺再摄取抑制剂(SSRI)后的情况的调控程序的指挥。埃文·德内里斯博士将指导首席研究员的科学发展，他是大脑5-羟色胺神经递质系统分子遗传学领域公认的领导者。他在了解生命周期中调节5-羟色胺系统功能的遗传机制以及这些机制如何影响5-羟色胺调节行为方面做出了基础性贡献。他的研究已经确定了Pet-1转录因子，该转录因子在胚胎调控网络中发挥作用，以指定小鼠腹侧后脑中的5-羟色胺神经元。Deneris博士是神经科学系的教授，培养了许多研究生和博士后研究员。此外，由备受尊敬的CWRU调查人员组成的咨询委员会将提供科学和职业指导。利用BAC转基因工具，通过识别Pet-1顺式调节区，在发育中的和成年大脑5-羟色胺神经元中指导转基因基因的高度重复性表达，Deneris博士开发了ePet-EYFP转基因小鼠系，其5-羟色胺神经元在整个生命周期内都被增强的黄色荧光蛋白(EYFP)基因标记。这些小鼠可以史无前例地接触到5-羟色胺神经元，并在生命的任何阶段进行专门针对5-羟色胺神经元的基因表达研究。拟议的实验将要求怀孕的ePet-EYFP小鼠产前暴露于SSRI，氟西汀。随后，将使用行为分析和分子技术来检测后代的表型。其具体目的包括：1)建立ePet-EYFP小鼠作为产前SSRI暴露所致行为发病的有效模型；2)研究产前SSRI暴露对ePet-EYFP小鼠的分子效应。EPet-EYFP小鼠的行为和分子相结合的方法在基础心理健康研究中是独一无二的。他们将共同测试首席研究员的假设，即产前SSRI暴露将导致5-羟色胺神经元发育调控程序的扰动导致行为发病。

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.