Cortical and Cognitive Development Following Synthetic Progestin Exposure

接触合成孕激素后的皮质和认知发育

• 批准号: 10183276
• 负责人: CHRISTINE K WAGNER
• 金额: $ 31.73万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-08 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10183276
• 关键词: 3-Dimensional; Acute; Adolescence; Adult; Animals; Attention; Attention deficit hyperactivity disorder; Awareness; Behavior; Behavioral; Behavioral inhibition; Benefits and Risks; Blood; Brain; Caproates; Cell Nucleus; Cells; Child; Childhood; Clinical; Cognitive; Complex; Core Facility; Decision Making; Development; Dopamine; Dopaminergic Cell; Dorsal; Dose; Evaluation; Exposure to; Fiber; High Pressure Liquid Chromatography; Human; Hydroxyprogesterone; Hyperactivity; Impaired cognition; Impairment; Impulsivity; Incidence; Infant; Investigation; Knowledge; Laboratory Rat; Learning Disabilities; Life; Light; Mass Spectrum Analysis; Measures; Medial; Mediating; Midbrain structure; Modeling; Mothers; Neonatology; Nuclear; Outcome; Pathway interactions; Perinatal; Pharmaceutical Preparations; Placenta; Play; Prefrontal Cortex; Pregnancy; Pregnant Women; Premature Birth; Premature Infant; Prevention; Progesterone; Progesterone Receptors; Progestins; Proteomics; Psyche structure; Publishing; Rattus; Risk; Risk-Taking; Rodent Model; Role; Serotonergic System; Serotonin; Serum; Synthetic Progestogens; Testing; Time; Universities; Ventral Tegmental Area; Woman; cognitive development; cognitive function; density; discounting; dopamine system; executive function; experimental study; fetal; flexibility; frontal lobe; in utero; nerve supply; neurochemistry; neurodevelopment; novel; peer; postnatal; prenatal exposure; prepulse inhibition; prevent; raphe nuclei; steroid hormone; synaptic pruning; synaptogenesis

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. Previous findings 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, the mesocortical serotonin pathway, and subsequent complex cognitive behaviors mediated by these circuits using a rodent model. Aim 1 will utilize HPLC/Mass Spec to quantify 17P levels in blood and brain following the administration of behaviorally-effective doses. Aim 2 will test the hypothesis that exposure to 17P during development will alter the number of dopaminergic cells in the midbrain ventral tegmental area, the number of serotonergic cells in the raphe nuclei, and will alter the density of dopaminergic and serotonergic fibers within the medial prefrontal and orbitofrontal cortex. Aim 3 will test the hypothesis that exposure to 17P during postnatal life will alter cognitive and executive function behaviors mediated by these pathways. Specifically, cognitive flexibility, attentional processing and sensorimotor gating, behavioral inhibition/impulsivity, impulsive decision making, hyperactivity, and risk taking behavior will be assessed in adolescence and adulthood in rats exposed to 17P during development. 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.

给孕妇服用合成孕激素以预防 近年来早产急剧增加。尽管这种增长， 关于合成孕激素对发育中的 个脑袋先前在啮齿动物模型中的发现表明，孕激素可能在 额叶皮层和皮层中多巴胺系统的发展， 注意力缺陷多动障碍（ADHD）的神经化学途径。 本提案的目的是审查接触合成的 孕激素、17α-羟孕酮己酸酯在中皮质发育中的作用 多巴胺通路、中皮层5-羟色胺通路和随后的复合物 通过啮齿动物模型研究这些回路介导的认知行为。目标1将利用 HPLC/质谱定量给药后血液和脑中的17 P水平 行为有效剂量。目标2将检验暴露于17 P 会改变中脑腹侧多巴胺能细胞的数量 被盖区，中缝核中的肾上腺素能细胞的数量，并将改变 内侧前额叶内多巴胺能和多巴胺能纤维的密度， 眶额皮质目的3将检验出生后暴露于17 P的假设， 生命将改变由这些途径介导的认知和执行功能行为。 具体而言，认知灵活性，注意力处理和感觉运动门控， 行为抑制/冲动、冲动决策、多动和风险 将在暴露于17 P的大鼠的青春期和成年期评估服用行为 在发展过程中。这些动物研究的结果将大大增加我们的 关于暴露于维生素E的潜在影响的知识， 未来关于子宫内儿童暴露结果的研究假设。