Synthetic Progestin Exposure & Mesocortical Dopamine System Development

描述(由申请人提供)：近年来，为预防早产而给孕妇服用合成孕激素的情况急剧增加。尽管有这种增加，但人们对合成孕激素对发育中的大脑的潜在影响知之甚少。来自啮齿动物模型的初步数据表明，孕激素可能在额叶皮质和中皮质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。这项建议的目的是利用啮齿动物模型研究人工孕激素17α-羟孕酮己酸酯对大脑皮层多巴胺通路和随后复杂认知行为发展的影响。目的1验证发育过程中暴露于17P会改变中脑腹侧被盖区多巴胺能细胞数量和改变内侧前额叶皮质多巴胺能纤维密度的假说。目标2将检验假设，在出生后生活中暴露于17P将 改变工作记忆(新物体识别)、行为抑制/冲动(抑制回避任务)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孕激素暴露的潜在影响的了解，从而为未来关于子宫内暴露的儿童结局的研究产生具体的假设。

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.