Prostaglandins and Cerebellum Development

前列腺素和小脑发育

基本信息

批准号：
9926725
负责人：
MARGARET M. MCCARTHY
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-23 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9926725
关键词：
Acute Adolescence Adolescent Adult Affective Amygdaloid structure Animals Area Aromatase Attentional deficit Behavior Behavioral Biological Biological Assay Brain Candidate Disease Gene Cells Cerebellum Code Cognition Cognitive Communication Data Development Dinoprostone Disease Environmental Risk Factor Enzymes Epigenetic Process Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Feedback Female Future Gap Junctions Gene Expression Gene Expression Profile Generations Genes Growth Hormonal Hormones Hyperactive behavior Image Immune Impairment In Vitro Inflammation Inflammatory Laboratory Rat Learning Life Maintenance Masculine Mediating Mediator of activation protein Memory Messenger RNA Microglia Modification Morphology Motor Neonatal Neurons Onset of illness Pathology Pathway interactions Pattern Play Predisposition Prefrontal Cortex Process Production Proprioception Prostaglandin Production Prostaglandins Purkinje Cells Reflex action Regulation Rest Role Schizophrenia Secondary to Signal Pathway Signal Transduction Social Behavior Source Steroids Structure Testing Therapeutic Therapeutic Intervention Time autism spectrum disorder cell growth disorder risk early onset genome-wide interest male methylome neuroinflammation neuron development neuropsychiatric disorder postnatal prevent response sample fixation sex social somatosensory trait translation to humans

项目摘要

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.

小脑的病理是社交、沟通、认知和情感的主要贡献者与发育中的神经精神疾病相关的缺陷包括自闭症。谱系障碍、注意力缺陷和多动症以及早发性精神分裂症。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，该表达谱容易失调具体来说，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。产后第二周是一个敏感期，在此期间对该通路的干扰会损害社交游戏分析揭示的神经发育和长期行为缺陷的结果，由于未知的原因，认知和体感阈值会出现行为缺陷。男性中敏感期的定义是编码基因的表达达到峰值。出生后第二周的芳香酶（Cyp19a）和雌激素受体（Esr1）是小胶质细胞。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中的一周，小胶质细胞都会对 PGE2 做出反应并产生 PGE2，从而产生积极的影响。初步研究结果表明，敏感期的炎症损伤会诱发这种情况。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。数据表明，男性的持久炎症更为严重，因此我们进一步应对这一问题。男性的行为变化是持久炎症的继发因素，我们将对此进行测试。 SA1 中的假设以及 SA2 中持久炎症的综合特征。我们确定了小胶质细胞在建立和维持持久炎症中的作用。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全基因组甲基化组的最终目标 SA4 决定了是否具有更大的脆弱性。男性是由早期激素介导的大脑性别分化编码的。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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Morphological and Phagocytic Profile of Microglia in the Developing Rat Cerebellum.

DOI：
10.1523/eneuro.0036-15.2015
发表时间：
2015-07
期刊：
eNeuro
影响因子：
3.4
作者：
Perez-Pouchoulen M;VanRyzin JW;McCarthy MM
通讯作者：
McCarthy MM

Regulatory Control of Microglial Phagocytosis by Estradiol and Prostaglandin E2 in the Developing Rat Cerebellum.

发育中的大鼠小脑中雌二醇和前列腺素 E2 对小胶质细胞吞噬作用的调节控制。

DOI：
10.1007/s12311-019-01071-z
发表时间：
2019
期刊：
Cerebellum (London, England)
影响因子：
0
作者：
Perez-Pouchoulen,Miguel;Yu,StaceyJ;Roby,ClintonR;Bonsavage,Nicole;McCarthy,MargaretM
通讯作者：
McCarthy,MargaretM