Sex differences in neuroimmune function and developmental vulnerability to early life traumatic brain injury

神经免疫功能的性别差异和早期创伤性脑损伤的发育脆弱性

• 批准号: 10578379
• 负责人: Kathryn M. Lenz
• 金额: $ 41.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578379
• 关键词: 10 year old; 4 year old; Acute; Adolescent; Adult; Affect; Alcohol abuse; Anxiety; Astrocytes; Attention deficit hyperactivity disorder; Behavioral; Blood - brain barrier anatomy; Brain; CSF1R gene; Cells; Child; Childhood; Chronic; Cognitive deficits; Data; Development; Drug abuse; Elderly; Elements; Emergency department visit; Environment; FDA approved; Female; Future; Gene Expression; Genes; Gliosis; Hippocampus; Histology; Hormones; Human; Hypothalamic structure; Immune; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knowledge; Lateral; Learning; Life; Mediating; Mediator; Mental Depression; Mental disorders; Microglia; Modeling; Moods; Neuroimmune; Neurological outcome; Neurons; Outcome; Patients; Pattern; Phase; Public Health; Rattus; Risk; Risk Taking; Rodent; Role; Sex Differences; Shapes; Signal Transduction; Social Behavior; Social Functioning; Source; Stress; Stress and Coping; Substance abuse problem; Synapses; Testing; Time; Toddler; Traumatic Brain Injury; Vascular Permeabilities; Withdrawal; Work; age group; behavior change; behavioral health; behavioral outcome; biological sex; blood-brain barrier disruption; blood-brain barrier permeabilization; brain cell; cell type; comparison group; early childhood; early experience; experience; experimental study; first responder; fluid percussion injury; improved; inhibitor; injured; male; mast cell; nano-string; nervous system disorder; neural circuit; neurobehavioral; neurodevelopment; neuroinflammation; neuropathology; novel; novel therapeutics; pediatric emergency; pediatric traumatic brain injury; pharmacologic; postnatal; preclinical study; public health relevance; response; response to brain injury; response to injury; sex; social; social deficits; social stress; transcriptome sequencing; transcriptomics; treatment strategy; verbal

Project summary: Traumatic brain injury (TBI) in childhood is the leading cause of pediatric emergency room visits, with over 800,000 children visiting the ER each year according to the CDC. Pediatric TBI can have lifelong consequences for behavioral health, increases rates of ADHD, drug and alcohol abuse, long-term cognitive and social deficits, depression and anxiety. This suggests that early childhood is a period of particular vulnerability to long-term, deleterious neurological outcomes after TBI. Despite the clear evidence of a significant public health problem, the proximal mechanisms leading up to those long term TBI-related outcomes are poorly understood. TBI induces robust neuroinflammation and brain-resident innate immune cells, such as microglia, regulate normal brain development, including synaptic patterning. The impact of TBI on microglia-synaptic interactions is poorly understood. We have demonstrated dramatic developmental biases in activation and sex differences in the profile of neuroimmune cells in the immature rat brain, both microglia and the less studied mast cells. Mast cells are abundant in the developing brain and sparse in adults, suggesting that mast cells could contribute uniquely to the neuroimmune milieu after pediatric TBI. Mast cells are ‘first responders’ to immune insults and coordinate subsequent immune cell (microglia and astrocyte) activation as well as vascular permeability but their role in TBI has not been well studied. In our project, we will use lateral fluid percussion injury on juvenile rats to model pediatric TBI, which our preliminary data suggest elicits robust mast cell activation in the hippocampus, acute gliosis, and long-term, sex-dependent shifts in social behavior and stress hormones. Because so little is known about the unique pediatric response to injury, we will compare the pediatric versus adult injury response of male and female rats via RNAseq and Nanostring profiling of isolated immune cells in a comprehensive time course study (Aim 1). To test for a contribution of mast cells to pediatric TBI, we will use an acute mast cell inhibition using an FDA-approved pharmacological agent and comprehensively profile neuroinflammatory responses, alterations in blood brain barrier (BBB) permeability to narrow in on a potential mechanism through which mast cells are acting after TBI, and correlate BBB changes with social and stress-related behavior outcomes (Aim 2). To determine whether microglia are important for long-term neurodevelopmental programming of behavioral outcomes and sculpting neural circuits after pediatric TBI, we will perform microglia depletion/forced turnover experiments post-TBI (Aim 3). We will compare sexes in all studies, and we predict that males more robust basal neuroimmune tone in the developing brain may render them more vulnerable to TBI-related outcomes. Our studies have the potential to improving long-term outcomes following pediatric traumatic brain injury and uncover potential new therapeutic options targeted to the unique neuroimmune environment of the developing brain.

项目概述：儿童期创伤性脑损伤（TBI）是儿科急诊的主要原因 根据疾病预防控制中心的数据，每年有超过80万儿童到急诊室就诊。小儿TBI可能有 行为健康的终身后果，增加ADHD，药物和酒精滥用，长期 认知和社交缺陷，抑郁和焦虑这表明，幼儿期是一个特殊的时期， TBI后长期、有害的神经系统结果的脆弱性。尽管有明确的证据表明， 严重的公共卫生问题，导致这些长期TBI相关的近端机制 结果知之甚少。TBI诱导强烈的神经炎症和脑固有免疫 细胞，如小胶质细胞，调节正常的大脑发育，包括突触模式。TBI的影响 对小胶质细胞-突触相互作用的研究知之甚少。我们已经证明了戏剧性的发展偏见 在未成熟大鼠大脑中神经免疫细胞的激活和性别差异中，小胶质细胞和神经胶质细胞都是 和研究较少的肥大细胞。肥大细胞在发育中的大脑中很丰富，而在成年人中很稀少， 这表明肥大细胞可能对儿童TBI后的神经免疫环境有独特的贡献。肥大细胞 是免疫损伤的“第一反应者”，并协调随后的免疫细胞（小胶质细胞和星形胶质细胞） 活化以及血管渗透性，但它们在TBI中的作用尚未得到充分研究。在我们的项目中， 使用幼年大鼠的侧向液压冲击损伤来建立儿童TBI模型，我们的初步数据表明， 海马中肥大细胞的激活，急性神经胶质增生，以及长期的，性别依赖性的变化， 社会行为和压力荷尔蒙因为我们对儿科对损伤的独特反应知之甚少， 我们将通过RNAseq和Nanostring比较雄性和雌性大鼠的儿科与成人损伤反应 在综合时程研究中分析分离的免疫细胞（Aim 1）。测试是否有 肥大细胞的儿科TBI，我们将使用急性肥大细胞抑制使用FDA批准的药理学 代理和全面的轮廓神经炎症反应，改变血脑屏障（BBB） TBI后肥大细胞通过其作用的潜在机制， BBB随着社会和压力相关行为结果而变化（目的2）。为了确定小胶质细胞是否 对行为结果的长期神经发育编程和塑造神经回路很重要 在小儿TBI后，我们将进行TBI后小胶质细胞耗竭/强迫更新实验（目的3）。我们将 比较所有研究中的性别，我们预测，男性更强大的基础神经免疫基调， 发育中的大脑可能使他们更容易受到TBI相关结果的影响。我们的研究有可能 改善小儿创伤性脑损伤后的长期结局，并发现潜在的新治疗方法 针对发育中大脑独特的神经免疫环境的选择。