Prostaglandins and Cerebellum Development

小脑的病理是导致社交、交流、认知和情感障碍的主要因素。 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，男性是主要的生物学风险。 预测器利用实验室大鼠，我们已经确定了一个以前未知的敏感期小脑 涉及内在基因表达谱的发展，该基因表达谱产生了对失调的脆弱性 通过炎症。具体地说，在健康的小脑中，前列腺素PGE2刺激芳香化酶 导致雌二醇产生增加和浦肯野神经元生长调节的酶。的 出生后第2周是一个敏感期，在此期间该通路的扰动会损害浦肯野氏病 神经元发育并导致长期行为缺陷， 认知和躯体感觉阈值。由于不了解的原因，行为缺陷是 在男性中更大。敏感期由编码以下两种基因的表达峰值限定： 芳香化酶（Cyp19a）和雌激素受体（Esr1）在出生后第2周。小胶质细胞是 我们还发现，"半活化"的小胶质细胞在出生后第二天达到高峰， 健康的小脑中的一周。小胶质细胞都响应并产生PGE2， 反馈回路初步研究结果表明，在敏感期的炎症损伤诱导 至少在青春期后期才能检测到的持久炎症，导致我们的总体疾病 假设：敏感期的炎症会产生持久的炎症， 由过度活跃的小胶质细胞介导，并改变小脑的发育轨迹。试点 数据显示，男性的持久性炎症更为严重。因此，我们进一步假设， 雄性的行为变化是继发于持久的炎症。我们将测试这些 SA 1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 探讨了在候选基因水平上持久炎症的表观遗传基础， 小胶质细胞的全基因组甲基化。最后的目标，SA4，确定是否更大的脆弱性， 男性是由大脑的早期神经介导的性别分化编码的。治疗 干预措施，无论是建立或逆转持久炎症的维持 在多个目标中进行了探索，并为未来翻译给人类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.