Cortical and Cognitive Development Following Synthetic Progestin Exposure

给孕妇服用合成孕激素以预防 近年来，早产现象急剧增加。尽管出现了这种增长， 人们对合成孕激素对发育的潜在影响知之甚少 大脑。先前在啮齿动物模型中的发现表明，孕激素可能在 额叶皮质和中皮质多巴胺系统的发育 注意缺陷多动障碍(ADHD)的神经化学途径。 这项建议的目的是检查暴露于合成的 孕酮、17α羟孕酮己酸酯在中皮质发育中的作用 多巴胺途径、中皮质5-羟色胺途径和随后的复合体 使用啮齿动物模型，通过这些回路调节认知行为。目标1将利用 高效液相色谱/质谱仪测定给药后血液和脑中17P的水平 行为有效剂量的比例。目标2将检验暴露于17P的假设 在发育过程中会改变中脑腹侧多巴胺能细胞的数量 中缝核团中5-羟色胺能细胞的数量，并将改变 前额内侧和5-羟色胺能纤维的密度 眶前叶皮质。目标3将检验出生后暴露于17P的假设 生活将改变由这些途径介导的认知和执行功能行为。 具体地说，认知灵活性、注意处理和感觉运动门控， 行为抑制/冲动、冲动决策、多动和风险 将评估暴露于17P的大鼠在青春期和成年期的摄取行为 在开发过程中。这些动物研究的结果将极大地增加我们的 关于孕激素暴露的潜在影响的知识 关于宫内暴露儿童结局的未来研究的假设。

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.