Prostaglandins and Cerebellum Development

小脑的病理是导致社交、交流、认知和情感的主要因素 与起源于发育的神经精神障碍相关的缺陷。其中包括自闭症。 谱系障碍、注意力缺陷和多动症以及早发性精神分裂症。神经性炎症 生命早期是这些疾病的主要环境风险，而男性是主要的生物学风险 预言者。利用实验室大鼠，我们在小脑中发现了一个以前未知的敏感期。 一种涉及内在基因表达谱的发育，这种基因表达谱易受调节失调的影响 由炎症引起。具体地说，在健康的小脑中，前列腺素PGE2刺激芳香酶 导致雌二醇量增加和调节浦肯野神经元生长的酶。这个 出生后第2周是一个敏感期，在这段时间内该通路的干扰会损害浦肯野。 通过社交游戏的分析揭示了神经元的发育和导致长期行为缺陷， 认知和躯体感觉阈值。由于尚不清楚的原因，行为缺陷 男性的比例更高。敏感期是由两种编码基因的表达高峰来定义的 芳香酶(Cyp19a)和雌激素受体(ESR1)在出生后2周。小胶质细胞是 脑部先天免疫细胞，我们还发现“半激活”的小胶质细胞在出生后第2天达到高峰 在健康的小脑中度过一周。小胶质细胞既对PGE2作出反应，又产生PGE2，从而产生积极的 反馈环路。初步研究结果表明，敏感时期的炎性侮辱会导致 至少在青春期后期都可以检测到的持久炎症，导致我们的 假设：敏感时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，改变了小脑的发育轨迹。引航员 数据表明，男性的持续性炎症更为严重。因此，我们进一步假设 男性的行为变化仅次于持久的炎症。我们将测试这些 SA1中的假设，全面描述了两性持久炎症的特征。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 在候选基因水平上探索持久炎症的表观遗传学基础 小胶质细胞的全基因组甲基组。最终目标SA4决定了更大的脆弱性是否 男性是由早期荷尔蒙调节的大脑性别分化来编码的。治疗性的 阻止或逆转持久炎症形成或维持的干预措施 在多个目标上进行了探索，并为未来对人类的翻译提供了一条明确的道路。

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.