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）：许多脑部疾病在患病率上显示出强烈的性别偏见，这表明大脑中正常的性别差异可能有助于其病因。这一提议的主要目标是了解大脑性别差异背后的神经机制，以阐明性别特异性发育如何产生易受特定脑部疾病影响的大脑。我们的实验室已经确定了视前区（POA）的性别分化是由脂质分子前列腺素E2调节的，POA是参与生殖行为的关键脑区。前列腺素与脑损伤或感染反应中的促炎信号有关，但它们在POA的正常突触发育中也起关键作用。我们建议研究小胶质细胞在POA性别分化中的作用，因为在脑炎症和损伤的背景下，小胶质细胞既是前列腺素的来源，也是对前列腺素的反应。小胶质细胞是大脑中的初级免疫能力细胞，在发育中的大脑中也处于主要激活状态，这表明它们有助于正常的大脑发育和可塑性。两个特定的目的将测试几个假设：1)在发育中的视前区是否存在小胶质细胞数量、活性或细胞因子信号的性别差异；2)新生儿小胶质细胞抑制是否会破坏视前区形态上的性别分化，从而导致性别特异性行为。这些实验将深入了解神经系统、内分泌系统和免疫系统之间的相互作用，从而产生性别特异性的大脑发育。