Novel Roles of Placental Allopregnanolone in Brain Development and Injury

摘要 胎盘功能受损与胎儿发育异常密切相关，尤其是大脑发育异常。 大脑发育异常或胎儿脑损伤会导致终生神经损伤，包括脑瘫， 癫痫发作和精神残疾。胎盘功能障碍可能使数以千计的胎儿面临终生风险 每年的减损。绝大多数将胎盘受损与胎儿脑损伤联系起来的研究 专注于气体交换或营养规划，忽视了胎盘的基本神经内分泌 角色。使用新的分子模型，我们正在检验我们的总体假设，即关键的胎盘激素 有助于正常的大脑发育，而它们的丢失会造成伤害。这样一个关键的胎盘 激素是别孕酮(allopregnanolone，ALLO)，是孕酮衍生的最有效的GABA能神经类固醇。在……里面 无论是啮齿动物还是人类妊娠，ALLO主要是由胎盘造成的。我们的初步实验 研究表明，妊娠期间药物作用下的Allo减少会扰乱大脑皮质-海马区的回路 成熟并改变GABA能亚基的表达。此外，内源性和外源性Allo提供 多种临床前损伤模型中的神经保护。然而，使用Allo作为围产期治疗剂，它 对于了解Allo在妊娠中的具体来源、生理水平和作用至关重要。到目前为止， 这些研究由于缺乏设计来精确改变和测量胎盘的工具而受到限制 神经类固醇，通过新一代小鼠模型和使用先进的 质谱学。我们已经生成了小鼠模型，在这些模型中，Allo的生产只在 胎盘。这些模型首次允许直接操纵胎盘类固醇。我们已经证明了 抑制胎盘异体生成可导致增殖中间产物的特异性减少 妊娠期间皮质脑室下区的祖细胞(IPC)，并有长期存在的 同种异体胎盘抑制后的功能性神经改变。使用我们新的绒毛鼠标模型 (AKR1c14fl/fl)，其中3αhsd的基因可以以组织特异性的方式缺失，我们将确定 胎盘异位基因在以下方面起关键作用：1)皮质生成；2)长期行为和回路功能； (3)可用于围产期治疗的损伤。阐明其作用机制 胎盘激素，包括Allo，塑造正常和异常的皮质发育 从根本上改变我们对大脑发育障碍和胎盘在形成中的作用的理解 长期的神经学结果。这些实验也提供了预防或改善 通过基于胎盘激素的新疗法来治疗发育性脑损伤。

ABSTRACT Compromised placental function is highly associated with abnormal fetal development, especially of the brain. Abnormal brain development or fetal brain injury leads to life-long neurological impairments, including cerebral palsy, seizures and mental disabilities. Placental dysfunction may place many thousands of fetuses at risk of life-long impairments each year. The vast majority of research connecting placental compromise to fetal brain injury has focused on gas exchange or nutritional programming, neglecting the placenta's essential neuroendocrine role. Using new molecular models, we are testing our overall hypothesis that key placental hormones contribute to normal brain development and that their loss contributes to injury. One such critical placental hormone is allopregnanolone (ALLO), the most potent GABAergic neurosteroid derived from progesterone. In both rodent and human gestation, ALLO is made predominantly by the placenta. Our preliminary experiments have shown that pharmacological ALLO reduction during gestation disrupts cortico-hippocampal circuit maturation and alters GABAergic subunit expression. Additionally, endogenous and exogenous ALLO provides neuroprotection in multiple preclinical injury models. To use ALLO as a perinatal therapeutic agent, however, it is critical to understand the specific source, physiological levels and actions of ALLO in gestation. Until now, these investigations have been limited by lack of tools designed to precisely alter and measure placental neurosteroids, barriers we have overcome through generation of new mouse models and use of advanced mass spectroscopy. We have generated mouse models in which ALLO production is suppressed only in placenta. These models allow direct placental steroid manipulation for the first time. We have shown that suppression of placental ALLO production results in a specific reduction of proliferating intermediate progenitor cells (IPCs) in the cortical subventricular zone during gestation and that there are long-lasting functional neurological alterations after placental ALLO is suppressed. Using our new floxed mouse model (AKR1c14fl/fl) in which the gene for 3αHSD can be deleted in a tissue-specific manner, we will determine the extent to which placental ALLO is critical to: 1) corticogenesis; 2) long-term behavior and circuit function; and 3) injury that may be amenable to perinatal treatment. Elucidation of the mechanisms by which placental hormones, including ALLO, shape normal and abnormal cortical development would fundamentally change our understanding of developmental brain disorders and the placenta's role in shaping long-term neurological outcomes. These experiments also provide the possibility to prevent or ameliorate developmental brain injury through novel therapies based on placental hormones.