Prostaglandins and Cerebellum Development

小脑的病理是社交、沟通、认知和情感的主要贡献者 与发育起源的神经精神疾病相关的缺陷。这些包括自闭症 谱系障碍、注意力缺陷和多动症以及早发性精神分裂症。神经炎症 生命早期是这些疾病的主要环境风险，而男性则是主要的生物学风险 预测器。利用实验室大鼠，我们发现了小脑中一个以前未知的敏感期 涉及内在基因表达谱的发育，该表达谱容易出现失调 通过炎症。具体来说，在健康的小脑中，前列腺素 PGE2 会刺激芳香酶 酶导致雌二醇产生增加并调节浦肯野神经元的生长。的 产后第二周是敏感期，在此期间该通路的扰动会损害浦肯野病 神经元发育和社交游戏分析揭示的长期行为缺陷的结果， 认知和体感阈值。由于未知的原因，行为缺陷是 男性较多。敏感期由编码基因的表达峰值定义 产后第二周的芳香酶 (Cyp19a) 和雌激素受体 (Esr1)。小胶质细胞是 大脑先天免疫细胞，我们还发现“半激活”的小胶质细胞在出生后第二次达到峰值 健康小脑一周。小胶质细胞对 PGE2 做出反应并产生 PGE2，从而产生积极的作用 反馈循环。初步研究结果表明，敏感期的炎症损伤会诱发 持续的炎症至少到青春期后期才可检测到，从而导致我们的总体症状 假设：敏感期的炎症会产生持久的炎症，即 由过度活跃的小胶质细胞介导并改变小脑的发育轨迹。飞行员 数据表明，男性的持久炎症更为严重。因此我们进一步假设 男性的行为变化是继发于持久炎症的。我们将测试这些 SA1 中的假设具有两性持久炎症的综合特征。在SA2中 我们确定了小胶质细胞在建立和维持持久炎症中的作用。 SA3 探索候选基因水平上持久炎症的表观遗传基础和 小胶质细胞的全基因组甲基化组。最终目标 SA4 决定是否存在更大的脆弱性 男性是由早期激素介导的大脑性别分化编码的。治疗性 阻止持久炎症的形成或逆转其维持的干预措施 进行了多个目标的探索，并为未来向人类翻译提供了一条清晰的道路。

Pathologies of the cerebellum are leading contributors to social, communicative, cognitive and affective deficits associated with neuropsychiatric disorders with origins in development. These include autism spectrum disorders, attention deficit and hyperactivity and early onset schizophrenia. Neuroinflammation early in life is a leading environmental risk for these disorders and being male is a leading biological predictor. Using the laboratory rat we have identified a previously unknown sensitive period in cerebellar development that involves an intrinsic gene expression profile that creates a vulnerability to dysregulation by inflammation. Specifically, in the healthy cerebellum the prostaglandin PGE2 stimulates the aromatase enzyme leading to increased estradiol production and regulation of the growth of Purkinje neurons. The 2nd postnatal week is a sensitive period and perturbation of this pathway during that time impairs Purkinje neuron development and results in long-term behavioral deficits revealed by assays of social play, cognition and somatosensory thresholds. For reasons that are not understood, behavioral deficits are greater in males. The sensitive period is defined by a peak in expression of both the gene coding for aromatase (Cyp19a) and the estrogen receptor (Esr1) during the 2nd postnatal week. Microglia are the brains innate immune cells and we also find that “semi-activated” microglia peak during the 2nd postnatal week in the healthy cerebellum. Microglia both respond to and produce PGE2, creating a positive feedback loop. Initial findings suggest that an inflammatory insult during the sensitive period induces enduring inflammation that is detectable until at least late adolescence, leading to our overarching hypothesis: Inflammation during the sensitive period generates enduring inflammation that is mediated by over active microglia and alters the developmental trajectory of the cerebellum. Pilot data suggests enduring inflammation is more severe in males. Therefore we further hypothesize that behavioral changes in males are secondary to enduring inflammation. We will test these hypotheses in SA1 with a comprehensive characterization of enduring inflammation in both sexes. In SA2 we determine the role of microglia in both establishing and maintaining enduring inflammation. SA3 explores the epigenetic underpinnings of enduring inflammation at the candidate gene level and the genome-wide methylome of microglia. The final aim, SA4, determines whether the greater vulnerability of males is encoded by earlier hormonally-mediated sexual differentiation of the brain. Therapeutic interventions that either stop the establishment of or reverse the maintenance of enduring inflammation are explored in multiple aims and offer a clear path towards future translation to humans.