Hormonal Contraceptives and Adolescent Brain Development

项目总结 仅在美国就有1000万人使用激素避孕药(HC)。而HC已经玩过了 作为女性健康革命的重要角色，HC对大脑的影响还没有得到很好的研究， 尤其是在青春期，经常开始使用HC。迫切需要这种知识作为一种 最近越来越多的研究表明，使用HC，特别是在青少年中，与 随后使用抗抑郁药，更有可能发展为抑郁症，并增加自杀风险。 青春期是荷尔蒙调节大脑发育的关键时期。在大脑中拥有最多 青春期重要的成熟变化是前额叶皮质(PFC)，或内侧前额叶皮质 (MPFC)。由于PFC/mPFC的发展周期延长，其在 抑郁症，我们的中心假设是青少年接触避孕激素可能会加剧 通过干扰正常的PFC发育而导致情绪失调的风险。我们将采用日常管理 HC中常用的激素(乙炔雌二醇和左旋诺孕酮)对青春期大鼠的影响 与mPFC相关的内分泌、大脑和行为终端相互关联。感兴趣的特定领域 在这些研究中包括中枢类固醇激素水平和受体表达(AIM 1)、突触修剪和 小胶质细胞-突触相互作用(目标2)和行为结果的长期编程依赖于 MPFC，包括压力应对和认知灵活性(目标3)。这项申请中提出的研究是 创新是因为它研究了一种广泛使用的药物，但对其效果知之甚少 在女性生命的重要时期对大脑进行潜势塑造时的神经轨迹 发展很快。这项拟议的研究具有重要意义，因为它有望产生关于 青少年使用HC对女性PFC的影响最终，对HC的神经科学研究将会取得进展 妇女健康研究，是实现我们促进知识的长期目标的迫切需要的一步 性别特有的因素如何在一生中影响大脑。

PROJECT SUMMARY Hormonal contraceptives (HC) are used by 10 million people in the United States alone. While HC have played an important role in revolutionizing women’s health, the impact of HC on the brain have not been well studied, especially during adolescence when HC use often begins. There is a critical need for this knowledge as a growing number of recent studies suggest that use of HC, specifically among adolescents, is associated with subsequent antidepressant use, greater likelihood of developing depression, and increased suicide risk. Adolescence is a critical period of hormone-mediated brain development. Among the brain regions with the most significant maturational changes during adolescence is the prefrontal cortex (PFC), or medial prefrontal cortex (mPFC) in rodents. Because of the extended period of PFC/mPFC development and its well-known role in depression, our central hypothesis is that adolescent exposure to contraceptive hormones may exacerbate the risk for mood dysregulation by perturbing normal PFC development. We will employ daily administration of hormones commonly used in HC (ethinyl estradiol and levonorgestrel) to adolescent rats and examine interrelated endocrine, brain, and behavioral endpoints of relevance to the mPFC. Particular domains of interest in these studies include central steroid hormone levels and receptor expression (Aim 1), synaptic pruning and microglia-synaptic interactions (Aim 2), and long-term programming of behavioral outcomes dependent on mPFC, including stress coping and cognitive flexibility (Aim 3). The research proposed in this application is innovative because it investigates a widely used pharmaceutical for which there is little known about its effects on the brain during an important time of the female lifespan when the potential to shape the trajectory of neural development is high. The proposed research is significant because it is expected to generate knowledge about the effects of adolescent HC use on the female PFC. Ultimately, neuroscientific studies on HC will advance women’s health research and are a much needed step in achieving our long term goal of advancing knowledge of how sex specific factors influence the brain across the lifespan.