Microglia and Sex Differences in the Developing Brain

大脑发育中的小胶质细胞和性别差异

• 批准号: 8202473
• 负责人: Kathryn M. Lenz
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2012-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202473
• 关键词: Adult; Astrocytes; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biological; Brain; Brain Diseases; Brain Injuries; Brain region; Cell Count; Cells; Cytokine Signaling; Data; Dependence; Development; Dinoprostone; Disease; Dissociation; Encephalitis; Endocrine system; Epilepsy; Estradiol; Etiology; Eye; Female; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Immune system; Immunocompetent; Individual; Infection; Inflammatory; Laboratories; Lead; Life; Lipids; Mental Depression; Microglia; Microscopic; Migraine; Molecular; Morphology; Multiple Sclerosis; Neonatal; Nervous system structure; Neurons; Play; Predisposition; Preoptic Areas; Prevalence; Process; Production; Prostaglandins; Reproductive Behavior; Risk Factors; Role; Sex Behavior; Sex Bias; Sex Characteristics; Sex Differentiation; Signal Transduction; Source; Synapses; Techniques; Testing; autism spectrum disorder; behavior test; cell type; chronic pain; cytokine; inhibitor/antagonist; insight; male; nervous system disorder; neuromechanism; novel; prevent; research study; response to injury; sex

DESCRIPTION (provided by applicant): Many brain disorders show a strong gender bias in prevalence, suggesting that normal sex differences in the brain may contribute to their etiology. The broad goal of this proposal is to understand the neural mechanisms underlying sex differences in the brain, in order to elucidate how sex-specific development can produce a brain that is susceptible to specific brain disorders. Our laboratory has established that sexual differentiation of the preoptic area (POA), a key brain region involved in reproductive behavior, is regulated by the lipid molecule, prostaglandin E2. Prostaglandins are associated with proinflammatory signaling in the brain in response to injury or infection, however they also play a key role in normal synaptic development in the POA. We propose to investigate the role that microglial cells play in sexually differentiating the POA, as microglial cells are both a source of and responsive to prostaglandins in the context of brain inflammation and injury. Microglia, the primary immunocompetent cells in the brain, are also in a predominantly activated state in the developing brain, suggesting they contribute to normal brain development and plasticity. Two specific aims will test several hypotheses by determining 1) whether there are sex differences in microglial cell number, activity, or cytokine signaling in the developing preoptic area and 2) whether neonatal microglial inhibition disrupts the morphological sexual differentiation of the preoptic area and resulting sex-specific behaviors. These experiments will give insight into the interaction between the nervous, endocrine, and immune systems to produce sex-specific brain development. PUBLIC HEALTH RELEVANCE: A major predictor of an individual's susceptibility to any given neurological disorder is their sex: Males show much higher rates of autism spectrum disorders, ADHD, and epilepsy, whereas females show higher rates of migraine headaches, chronic pain, depression, and multiple sclerosis. Brain inflammation early in life is a risk factor for developing a neurological disorder. Studying the basic mechanisms through which sex differences in the brain are established and how inflammatory signaling contributes to brain development will provide insight into how sex-specific brain development can lead to vulnerability to brain abnormality and disorders.

描述（由申请人提供）：许多脑部疾病表现出强烈的性别偏见，表明大脑的正常性别差异可能会导致其病因。该提案的广泛目标是了解大脑中性别差异的神经机制，以阐明性别特异性发展如何产生对特定脑部疾病敏感的大脑。我们的实验室已经确定，脂质分子Prostaglandin E2调节了与生殖行为有关的关键大脑区域的性区分（POA）。前列腺素与响应损伤或感染的大脑促炎信号传导有关，但是它们在POA的正常突触发育中也起着关键作用。我们建议研究小胶质细胞在性别区分POA中起作用的作用，因为在脑部炎症和损伤的背景下，小胶质细胞既是对前列腺素的来源又是对前列腺素的反应。小胶质细胞是大脑中的原发性免疫能力细胞，也主要处于发育中的大脑中的激活状态，这表明它们有助于正常的脑发育和可塑性。两个具体目的将通过确定1）在发育前区域中的小胶质细胞数，活性或细胞因子信号传导以及2）新生儿小胶质细胞抑制是否会破坏preoptic区域的形态分化并导致性别特定行为的形态分化。这些实验将洞悉神经，内分泌和免疫系统之间的相互作用，以产生性别特定的大脑发育。 公共卫生相关性：个人对任何给定神经系统疾病的敏感性的主要预测指标是他们的性别：雄性表现出更高的自闭症谱系障碍，ADHD和癫痫病的率要高得多，而女性显示出偏头痛的率更高，慢性疼痛，慢性疼痛，抑郁症和多发性硬化症。生命早期脑部炎症是患有神经系统疾病的危险因素。研究建立大脑性别差异的基本机制以及炎症信号如何有助于大脑发育，将洞悉性别特异性大脑发育如何导致脑部异常和疾病的脆弱性。