Synthetic Progestin Exposure & Mesocortical Dopamine System Development

合成孕激素暴露

• 批准号: 8638090
• 负责人: CHRISTINE K WAGNER
• 金额: $ 18.75万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638090
• 关键词: 17p; ARHGEF5 gene; Adolescence; Adolescent; Adult; Animals; Attention; Attention deficit hyperactivity disorder; Behavior; Behavioral; Behavioral inhibition; Benefits and Risks; Brain; Cell Count; Cells; Child; Clinical; Cognitive; Complex; Data; Development; Dopamine; Dopaminergic Cell; Elderly; Exposure to; Female; Fiber; Growth; Health; High Pressure Liquid Chromatography; Human; Hydroxyprogesterone Caproate; Impulsivity; Incidence; Infant; Knowledge; Laboratory Rat; Learning Disabilities; Life; Light; Longevity; Mass Spectrum Analysis; Medial; Mediating; Memory; Midbrain structure; Modeling; Mothers; Nature; Neonatology; Nuclear; Outcome; Pathway interactions; Performance; Perinatal; Perinatal Exposure; Pharmaceutical Preparations; Pilot Projects; Placenta; Plasma; Play; Prefrontal Cortex; Pregnancy; Pregnant Women; Premature Birth; Premature Infant; Prevention; Progesterone; Progesterone Receptors; Progestins; Psyche structure; Rattus; Risk; Rodent Model; Role; Short-Term Memory; Synthetic Progestogens; Systems Development; Testing; Time; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Woman; density; dopamine system; fetal; flexibility; frontal lobe; in utero; innovation; male; nerve supply; neural circuit; neurochemistry; neurodevelopment; neuronal cell body; novel; object recognition; peer; postnatal; prevent; receptor; receptor function; relating to nervous system; research study; steroid hormone

DESCRIPTION (provided by applicant): The administration of synthetic progestins to pregnant women for the prevention of premature delivery has increased dramatically in recent years. Despite this increase, very little is known about the potential effects of synthetic progestins on the developing brain. Preliminary data from rodent models suggest that progestins may play a role in the development of frontal cortex and the mesocortical dopamine system, a neurochemical pathway implicated in Attention Deficit Hyperactivity Disorder (ADHD). The objective of this proposal is to examine the effects of exposure to the synthetic progestin, 17α-hydroxyprogesterone caproate in the development of the mesocortical dopamine pathway and subsequent complex cognitive behaviors using a rodent model. Aim 1 will test the hypothesis that exposure to 17P during development will alter the number of dopaminergic cells in the midbrain ventral tegmental area and will alter the density of dopaminergic fibers within the medial prefrontal cortex. Aim 2 will test the hypothesis exposure to 17P during postnatal life will alter working memory (Novel Object Recognition), behavioral inhibition/impulsivity (Inhibitory Avoidance Task) and cognitive flexibility (Set Shift Task). Results from these animal studies would vastly increase our knowledge about the potential effects of progestin exposure to generate specific hypotheses for future research regarding outcomes in children exposed in utero.

描述（由申请人提供）：近年来，向孕妇施用合成孕激素以预防早产的情况急剧增加。尽管这种增加，很少有人知道合成孕激素对大脑发育的潜在影响。来自啮齿动物模型的初步数据表明，孕激素可能在额叶皮层和中皮层多巴胺系统的发育中发挥作用，这是一种与注意缺陷多动障碍（ADHD）有关的神经化学途径。本提案的目的是使用啮齿动物模型检查暴露于合成的孕酮、17α-羟孕酮己酸酯对中皮质多巴胺通路和随后的复杂认知行为发育的影响。目的1将测试的假设，暴露于17 P在发展过程中会改变中脑腹侧被盖区的多巴胺能细胞的数量，并会改变内侧前额叶皮质内的多巴胺能纤维的密度。目的2将检验出生后生活期间暴露于17 P的假设， 改变工作记忆（新物体识别），行为抑制/冲动（抑制性回避任务）和认知灵活性（设置转移任务）。这些动物研究的结果将极大地增加我们对子宫内暴露的潜在影响的了解，从而为未来关于子宫内暴露儿童结局的研究产生具体的假设。