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.

项目摘要：童年时期的创伤性脑损伤（TBI）是小儿急诊室的主要原因 访问，根据疾病预防控制中心，每年有超过80万儿童访问急诊室。小儿TBI可以 终身对行为健康的后果，增加多动症，毒品和酒精滥用率，长期 认知和社会缺陷，抑郁和动画。这表明幼儿是一个特殊的时期 TBI之后的长期，有害神经结局的脆弱性。尽管有明确的证据表明 重大公共卫生问题，近端机制导致了与TBI相关的长期机制 结果知之甚少。 TBI诱导强大的神经炎症和脑居住的先天免疫 细胞（例如小胶质细胞）调节正常的脑发育，包括突触模式。 TBI的影响 在小胶质细胞上，突触相互作用知之甚少。我们已经证明了戏剧性的发展偏见 在未成熟大鼠脑中神经免疫细胞谱的激活和性别差异中，这两个小胶质细胞 和较少的肥大细胞。肥大细胞在发育中的大脑中丰富而成人稀疏， 表明肥大细胞可以在小儿TBI后对神经免疫性环境唯一贡献。肥大细胞 是“第一反应者”免疫侮辱并协调随后的免疫细胞（小胶质细胞和星形胶质细胞） 激活以及血管渗透性，但它们在TBI中的作用尚未很好地研究。在我们的项目中，我们将 在少年大鼠上使用侧液打击乐损伤以模拟小儿TBI，我们的初步数据表明了这一点 在海马，急性神经病中引起强大的肥大细胞激活以及长期的性依赖性转移 社会行为和压力恐怖。因为对损伤的独特小儿反应知之甚少，所以 我们将通过RNASEQ和纳米串比较小儿和雌性大鼠的儿科与成人损伤反应 在一项全面的时间课程研究中对孤立的免疫球的分析（AIM 1）。测试贡献 肥大细胞到小儿TBI，我们将使用FDA批准的药物使用急性肥大细胞抑制 代理和全面介绍神经炎症反应，血液脑屏障的改变（BBB） 在肥大细胞在TBI之后作用并相关的潜在机制狭窄的渗透性 BBB随社会和压力相关的行为结果而变化（AIM 2）。确定小胶质细胞是否是 对于行为结果和雕刻神经环路的长期神经发育编程很重要 小儿TBI之后，我们将进行TBI后TBI进行小胶质细胞耗竭/强制周转实验（AIM 3）。我们将 比较所有研究中的性别，我们预测男性在 发展大脑可能会使他们更容易受到与TBI相关的结果的影响。我们的研究有可能 小儿创伤性脑损伤并发现潜在的新疗法后，改善长期结局 针对发展中大脑独特的神经免疫环境的选项。